Room-temperature stable dronabinol formulations

ABSTRACT

A room temperature stable cannabinoid formulation is disclosed. In preferred embodiments, the cannabinoid formulation is dronabinol in an oil-based carrier contained within a hard gelatin capsule.

This application claims priority from U.S. Provisional PatentApplication No. 60/634,474, filed on Dec. 9, 2004, the disclosure ofwhich is hereby incorporated by reference in its entirety.

TECHNICAL FIELD

The present invention relates to formulations of cannabinoids which arestable at room temperature for extended periods of time, e.g., for twoyears or more. The present invention is further related to oralcannabinoid formulations which rapidly disintegrate when orallyadministered to human patients. The invention has utility in the fieldsof pharmaceutical formulation, pharmacology and medicine.

BACKGROUND OF THE INVENTION

Delta-9-Tetrahydrocannabinol (also known as THC, Dronabinol and D9THC)is a naturally occurring compound and is the primary active ingredientin the controlled substance marijuana. Marijuana refers to the driedflowers and leaves of Cannabis Sativa, the hemp plant. These parts ofthe plant contain several compounds called cannabinoids (includingDronabinol), that may help patients with certain disease conditions.Dronabinol has been approved by the Food and Drug Administration (FDA)for the control of nausea and vomiting associated with chemotherapy and,more recently, for appetite stimulation of AIDS patients suffering fromwasting syndrome. Synthetic dronabinol has been utilized as apharmaceutically active ingredient, and cannabis-based medicines usingbotanical sources of cannibis rather than synthetic THC are also knownin the art.

Currently, dronabinol is commercially available in the U.S. as asolution in a soft gelatin capsule under the tradename Marinol® fromUnimed Pharmaceuticals, Inc., which is orally administered. Upon oraladministration, the gelatin dissolves, releasing the drug. Thedronabinol dissolved in sesame oil, is then absorbed during its passagethrough the gastrointestinal tract. Marinol is indicated for thetreatment of: 1) anorexia associated with weight loss in patients withAIDS and 2) nausea and vomiting associated with cancer chemotherapy inpatients who have failed to respond adequately to conventionalantiemetic treatments. Marinol capsules are sold in 2.5 mg, 5 mg, or 10mg dosages and formulated with the following inactive ingredients:sesame oil, gelatin, glycerin, (glycerol), methylparaben, propylparaben,and titanium dioxide. The Marinol soft gelatin capsule form ofdronabinol is highly unstable at room temperature, and it is recommendedthat the product be stored at refrigerated (2-8° C.) or cool (8-15° C.)conditions (Marinol package label, Physicians Desk Reference®, ed.2003). Additionally, Marinol should be packaged in a well-closedcontainer and stored in a cool environment between 8° and 15° C. (46°and 59° F.). At the present time, dronabinol is the only approvedcannabinoid drug commercially available.

Other formulations containing dronabinol appear in the art. In 1976,Olsen et al. described a chlorofluorocarbon (CFC) propelled MDIformulation of dronabinol. Olsen, J. L., Lodge, J. W., Shapiro, B. J.and Tashkin, D. P. (1976) An inhalation aerosol of D9THC. J. Pharmacyand Pharmacol. 28:86. However, dronabinol is known to deteriorate duringstorage, and the stability of the dronabinol in this formulation issuspect. In addition, the ethanol content in this formulation was sohigh (about 23%) that an aerosol was created with droplets too large tobe effectively inhaled. See, Dalby, R. N. and Byron, P. R. (1988)Comparison of output particle size distributions from pressurizedaerosols formulated as solutions or suspensions. Pharm. Res. 5:36-39.The dronabinol CFC formulations were tested for use in treating asthmabut were shown to be only moderately effective. See, Tashkin, D. P.,Reiss, S., Shapiro, B. J., Calvarese, B., Olsen, J. L. and Lidgek, J. W.(1977) Bronchial effects of aerosolized D9THC in healthy and asthmaticsubjects. Amer. Rev. of Resp. Disease. 115:57-65; Williams, S. J.,Hartley, J. P. R. and Graham, J. D. P. (1976) Bronchodilator effect ofD9THC administered by aerosol to asthmatic patients. Thorax. 31:720-723.Moreover, CFC propellants have since been banned so that such aformulation is now useless.

U.S. Pat. No. 6,509,005 describes an aerosol-dispensable pharmaceuticalformulation comprising a hydrofluoroalkane propellant, (for example, HFA227 or HFA 134a) and dronabinol (D9THC), which formulation is said to bestable. The propellant is present in the range of approximately 78 to100% by weight, and more particularly the propellant is present in therange of approximately 85 to 100% by weight. An organic solvent such asethanol can be used to assist in solubilizing the dronabinol in thepropellant but is stated that it is not required. If a solvent is used,preferably less than 20% by weight will be required, and most preferablyless than 15% by weight will be required. The pharmaceutically effectiveconcentration of dronabinol is preferably in the range of 0.05 to 10% byweight.

U.S. Pat. No. 6,747,058 and U.S. Patent Application Publication No.2004/0162336 describe an aerosolizable formulation for delivery ofdelta-9-tetrahydrocannabinol in a semi-aqueous solvent, such as 35:10:55alcohol:water:propylene glycol (v/v), which is said to produce a stableclear solution near the solubility point of the drug.

U.S. Pat. No. 6,383,513 describes a composition for nasal deliverycomprising a cannabinoid in a biphasic delivery system, wherein thebiphasic delivery system is an oil-in-water emulsion.

U.S. Patent Application Publication No. 2003/0229027 describes a methodof preparing a pharmaceutical composition comprising a naturalcannabinoid compound such as delta-9-tetrahydrocannabinol which is saidto be stabilized which comprises such a compound and a glass of a sugar,a sugar alcohol, a mixture of sugars or a mixture of sugars alcohols.The natural cannabinoid compound is dissolved in an organic solvent thatis soluble in water and the sugar, sugar alcohol, mixture of sugars ormixture of sugar alcohols is dissolved in water; the dissolvedcannabinoid compound and the dissolved sugar(s) are mixed; and themixture is then dried by freeze drying, spray drying, vacuum drying, orsuper critical drying.

U.S. Pat. Nos. 5,508,037 and 5,389,375 describe suppository formulationsprepared by admixing a therapeutically effective amount of at least onedronabinol prodrug ester derivative with a suppository base which issaid to provide long term stability to the suppository formulation.

Dronabinol has been used as an antiemetic to relieve nausea and vomitingin patients receiving cancer chemotherapy. Additionally, U.S. Pat. No.6,703,418 describes a method of treating a patient with symptomatic HIVinfection to stimulate weight gain in the patient, which comprisesadministering to the patient a pharmaceutical composition comprisingdronabinol in an amount sufficient to cause an increase in weight of thepatient.

Despite all of the work outlined above and elsewhere, to date a roomtemperature stable oral dosage form of a cannabinoid such as dronabinolin a capsule has not been achieved.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of the present invention to provide a room temperaturestable cannabinoid drug product.

It is another object of the present invention to provide a roomtemperature stable formulation of a cannabinoid such as dronabinol(delta-9 tetrahydrocannabinol) which is orally administrable to mammals.

It is a further object of the invention to provide a room temperaturestable formulation of a cannabinoid such as dronabinol which is readilyavailable for absorption in any part of the gastrointestinal tract ofmammals, e.g., human subjects or patients.

It is a further object of the invention to provide a room temperaturestable formulation of a cannabinoid such as dronabinol which ishomogeneous and thermodynamically stable.

It is a further object of the invention to provide a room-temperaturestable cannabinoid formulation by utilizing liquid filled hard gelatintechnology.

It is a further object of the invention to provide a stabilizedcannabinoid formulation where the cannabinoid is contained in alipophilic medium such as an oil.

It is a further object of the invention to provide a stabilizedcannabinoid formulated in a lipophilic medium such as an oil which hasno inclusions or additives responsible for the instability ofcannabinoid contained therein.

In accordance with these and other objects and features, the presentinvention is directed in part to a room-temperature stable cannabinoidformulation comprising a hard gelatin capsule containing therapeuticallyeffective amount of a pharmaceutically acceptable cannabinoid in anoil-based carrier.

The invention is further directed to a cannabinoid dosage form,comprising an effective amount of a mixture of pharmaceuticallyacceptable cannabinoid and a pharmaceutically acceptable oil-basedcarrier, and a hard gelatin capsule encapsulating the mixture of thecannabinoid and the oil-based carrier.

The invention is further directed in part to a room-temperature stableformulation of a cannabinoid, comprising a therapeutically effectiveamount of a cannabinoid dispersed in an oil-based carrier contained in aunit dose enclosure, said unit dose enclosure composed of one or morematerials which do not react with the cannabinoid or allow substantialpermeation of oxygen and which effectively seals the cannabinoid frommoisture, such that the cannabinoid in the formulation is protectedagainst unacceptable degradation.

The invention is further directed in part to a formulation of atherapeutically effective amount of an encapsulated cannabinoid andmeans for stabilizing the cannabinoid.

The invention is further directed in part to a stabilized oral dosageform of a cannabinoid, comprising a mixture of a therapeuticallyeffective amount of a cannabinoid dispersed in an oil-based carriercontained in unit dosage form selected from a hard gelatin capsule, acellulosic capsule, a starch capsule, and a non-animal basedhydrocolloid film-forming composition.

The invention is further directed in part to a stabilized cannabinoiddosage form prepared by utilizing liquid filled hard gelatin technologyto obtain a dosage form.

The invention is further directed in part to a stabilized oral dosageform of a cannabinoid, comprising a therapeutically effective amount ofa cannabinoid dispersed in an oil-based carrier and encapsulated withina soft gelatin capsule, said oil-based carrier containing an effectiveamount of a stabilizer for the cannabinoid to provide a room-temperaturestable formulation for at least one year.

In further preferred embodiments of the invention where the formulationcontains dronabinol as the active ingredient, the dosage form containingingredients at a level selected from the following during its claimedshelf-life: (i) not less than 90% of the initial dronabinol content;(ii) not greater than about 2% cannabinol; (iii) not greater than about2% delta-8-THC; and any combination of the foregoing.

In certain preferred embodiments, the present invention provides acannabinoid formulation (e.g., dronabinol) that is stable at allconditions—refrigerated, cool and room temperature (2-8° C., 25° C./60%RH, 30° C./60% RH). In other words, in certain preferred embodiments,the stabilized cannabinoid formulations may be stored at ambienttemperature and humidity, or in a refrigerator, by the patient.

In certain preferred embodiments, the cannabinoid is dronabinolformulated in sesame oil-containing capsules. However, the cannabinoidformulations of the invention may also be in the form of liquids(including suspensions and emulsions), tablets, suppositories,transdermal formulations and sublingual formulations, as well asinjectable formulations.

In certain preferred embodiments, the invention is directed to astabilized oral dosage form of dronabinol, comprising from about 0.05 mgto about 20 mg dronabinol dispersed in sesame oil, the concentration ofdronabinol in the sesame oil being from about 1.5 to about 6% by weight,encapsulated in a sealed hard gelatin capsule.

The invention is further directed in part to a method for stabilizing anoral dosage form containing a cannabinoid; comprising incorporating atherapeutically effective amount of a cannabinoid dispersed in anoil-based carrier into a unit dosage form suitable for oraladministration, said unit dosage form consisting of a material selectedfrom a hard gelatin capsule, a cellulosic capsule, a starch capsule, anda non-animal based hydrocolloid film-forming composition.

The invention is further directed in part to a method for stabilizing adosage form containing a cannabinoid as the active pharmaceuticalingredient, comprising encapsulating a therapeutically effective amountof the cannabinoid in a pharmaceutically acceptable oil-based carriercontaining an effective amount of one or more anti-oxidants.

The invention is further directed in part to a method for stabilizing adosage form containing a cannabinoid as the active pharmaceuticalingredient, comprising encapsulating a therapeutically effective amountof the cannabinoid in a pharmaceutically acceptable oil-based carriercontaining an amount of one or more organic bases that is effective tostabilize the cannabinoid.

The invention is further directed in part to a method for preparing astabilized dosage form containing a cannabinoid as the activepharmaceutical ingredient, comprising

-   mixing a solution of a cannabinoid with an oil-based carrier to    obtain a flowable mixture;-   filling an appropriately-sized hard gelatin capsule with a quantity    of said mixture that contains a desired therapeutically effective    amount of said cannabinoid; and-   sealing the hard gelatin capsule.

The invention is further directed in part to a method for preparing astabilized dosage form containing a cannabinoid as the activepharmaceutical ingredient, comprising mixing a solution of a cannabinoidwith an oil-based carrier to obtain a flowable mixture; encapsulating aquantity of the mixture containing a desired therapeutically effectiveamount of said cannabinoid within a non-glycerin based compositioncomposed of one or more materials which do not react with thecannabinoid or allow substantial permeation of oxygen and whicheffectively seals the cannabinoid from moisture.

In certain preferred embodiments, the formulation contains at leastabout 80% w/w of the cannabinoid in undegraded form after exposure ofthe formulation to storage conditions selected from the group consistingof (i) 2-8° C., (ii) 25° C./60% relative humidity (RH) for 6 months;(iii) 30° C./60% relative humidity (RH) for 6 months; (iv) elevatedtemperature and humidity conditions of 40° C./75% relative humidity (RH)for 6 months; (v) elevated temperature conditions of 55° C. for twoweeks; (vi) room temperature (25° C.) for two years; and (vii) anycombination thereof

In certain embodiments, formulations and methods of the inventionprovide for the active pharmaceutical cannabinoid ingredient remainingwithin about 90 to about 110 percent of its original amount included inthe dosage form for at least 1 year, and preferably at least about 2years after manufacture.

In certain preferred embodiments, formulations of the invention arehomogeneous and thermodynamically stable.

In certain embodiments, the cannabinoid formulations of the inventioncomprise effective amounts of one or more stabilizers to promotestability of the cannabinoid against unacceptable degradation. Thestabilizers may comprise one or more anti-oxidants, one or more organicbases, and/or other stabilizers for cannabinoids known to those skilledin the art.

The invention is further directed in part to a method for stabilizing adosage form containing a cannabinoid as the active pharmaceuticalingredient, comprising encapsulating a therapeutically effective amountof the cannabinoid in a liquid filled hard gelatin capsule. In certainembodiments, the liquid comprises an oil-based carrier. In certainembodiments, the oil-based carrier further comprises one or morestabilizers for the cannabinoid (e.g, anti-oxidants, organic bases, orboth, as set forth more specifically herein).

In certain embodiments, the oil-based carrier is a triglyceride selectedfrom the group consisting of almond oil; babassu oil; borage oil;blackcurrant seed oil; canola oil; castor oil; coconut oil; corn oil;cottonseed oil; evening primrose oil; grapeseed oil; groundnut oil;mustard seed oil; olive oil; palm oil; palm kernel oil; peanut oil;rapeseed oil; safflower oil; sesame oil; shark liver oil; soybean oil;sunflower oil; hydrogenated castor oil; hydrogenated coconut oil;hydrogenated palm oil; hydrogenated soybean oil; hydrogenated vegetableoil; hydrogenated cottonseed and castor oil; partially hydrogenatedsoybean oil; soy oil; glyceryl tricaproate; glyceryl tricaprylate;glyceryl tricaprate; glyceryl triundecanoate; glyceryl trilaurate;glyceryl trioleate; glyceryl trilinoleate; glyceryl trilinolenate;glyceryl tricaprylate/caprate; glyceryl tricaprylate/caprate/laurate;glyceryl tricaprylate/caprate/linoleate; glyceryltricaprylate/caprate/stearate; saturated polyglycolized glycerides;linoleic glycerides; caprylic/capric glycerides; modified triglycerides;fractionated triglycerides; and mixtures thereof.

In certain embodiments, the oil-based carrier is selected from the groupconsisting of soybean oil, olive oil, cotton seed oil, peanut oil,sesame oil, castor oil, and mixtures of any of the foregoing. In certainpreferred embodiments, the oil-based carrier comprises sesame oil (e.g.,a Food Grade sesame oil or a NF grade sesame oil).

In certain embodiments wherein the oil-based carrier is sesame oil, thesesame oil contains an effective amount of an anti-oxidant selected fromthe group consisting of sesamin, sesamol, sesamolin, lecithin and anycombination of the foregoing (either already present in the (unpurified)sesame oil or added to purified sesame oil.

In certain embodiments, the oil-based carrier may comprise a semi-solidlipophilic material selected from the group consisting of arachis oil(Groundnut 36); castor oil (Cutina HR); cottonseed oil (Sterotex); palmoil (Softisan 154); soybean oil (Alkosol 407). In certain suchembodiments, an effective amount of a viscosity modifier may be includedto provide a pharmaceutically acceptable viscosity to the cannabinoiddispersed in the oil-based carrier. Such viscosity modifiers may be,e.g., Aerosil (silicon dioxide); cetostearyl alcohol; cetyl alcohol;stearyl alcohol; Gelucire 33/01; Gelucire 39/01; Gelucire 43/01;glyceryl behenate (Compritol 888 ATO); glyceryl palmitostearate(Precirol AT05); Softisan 100; Softisan 142; Softisan 378; Softisan 649;and mixtures thereof.

The invention is further directed to a dosage form wherein thecannabinoid is dronabinol and does not contain unacceptable levels ofdronabinol degradants in the dosage form selected from the groupconsisting of greater than 2% delta-8 tetrahydrocannabinol (D8THC),greater than 2% cannabinol (CBN), greater than 2% cannabidiol (CBD), andany combination thereof.

In certain preferred embodiments where the stabilizer comprises anorganic base, the dosage form may comprise from about 0.001% w/w toabout 5% organic base, preferably from about 0.007% w/w to about 2%organic base, by weight. In certain preferred embodiments, the organicbase is selected from the group consisting of ethanolamine,methanolamine, meglumine, and any combination of the foregoing.

In certain embodiments where the stabilizer is an anti-oxidant (such aslecithin), the dosage from may comprise from about 0.001% to about 10%,and more preferably from about 0.3% to about 8.25% anti-oxidant, byweight. In other embodiments where the anti-oxidant is L-ascorbicacid-6-palmitate, it may be included in an amount from about 0.001% toabout 15%, and preferably from about 0.01% to about 1% by weight.

The anti-oxidant included in the formulations of the invention mayfurther be selected from e.g., butyl hydroxyl anisole (BHA), butylhydroxyl toluene (BHT), propyl gallate, lecithin, Vitamin E tocopherol,sesamin, sesamol, sesamolin, alpha tocopherol, ascorbic acid, ascorbylpalmitate, fumaric acid, malic acid, sodium ascorbate and sodiummetabisulphite, disodium EDTA, and combinations of any of the foregoing.

In certain preferred embodiments, the dosage forms of the inventioncomprises from about 0.05% to about 90% cannabinoid, preferably fromabout 0.1% to about 50% cannabinoid, more preferably about 1.5% to about6% cannabinoid, and most preferably from about 2.5% to about 4.5%cannabinoid by weight.

In certain embodiments wherein the unit dose enclosure is a hard gelatincapsule, the capsule preferably contains from about 85% to about 100%gelatin and from about 1% to about 15% water, by weight.

The invention is further directed to a dosage form which furthercomprises one or more additional therapeutically active agents.Non-limiting examples of such additional therapeutically active agentsinclude a narcotic analgesic, a non-narcotic analgesic, an anti-emetic,a steroid, and mixtures of any of the foregoing.

In certain embodiments, formulations of the invention include furtherpharmaceutically acceptable excipients. Non-limiting examples of suchpharmaceutically acceptable excipients include solubilizers for saidcannabinoid, emulsifiers, absorption enhancers, a surfactants, etc.

In certain preferred embodiments, the cannabinoid formulations includedronabinol as the active pharmaceutical ingredient, preferably in anamount from about 0.05 mg to about 20 mg. In other embodiments, theformulations include from about 2.5 mg to about 20 mg dronabinol.

The term “pharmaceutically acceptable” is defined for purposes of theinvention as meaning that a particular ingredient (e.g., pharmaceuticalcarrier, excipient) is not biologically or otherwise undesirable in anoral dosage form, i.e., the amount of the compound in an orallyadministered composition or dosage form does not cause any undesirableeffects to the formulation or to the patient.

Testing for stability may be conducted, (e.g., for two year stabilitydetermination) by placing the dosage forms of the present inventionunder accelerated storage conditions of elevated temperature andhumidity of 40° C./75% relative humidity (RH) for 6 months, and/orplacing the dosage forms of the present invention under elevatedtemperature conditions of 55° C. for two weeks; and/or placing thedosage forms of the present invention in storage at room temperature(25° C.) under ambient relative humidity conditions for two years.

The phrase “does not degrade to an unacceptable extent” and the term“stable” as it applies to the cannabinoid formulations of the inventionis meant for purposes of the invention to mean that the formulationcontains at least about 80% w/w, and preferably at least about 90% w/wof the cannabinoid in undegraded form after exposure of the formulationto storage conditions selected from the group consisting of (i) 2-8° C.,(ii) 25° C./60% relative humidity (RH) for 6 months; (iii) 30° C./60%relative humidity (RH) for 6 months; (iv) 40° C./75% relative humidity(RH) for 6 months; (v) elevated temperature conditions of 55° C. for twoweeks; (vi) room temperature (25° C.) for at least one year (andpreferably at least about two years); and (vii) any combination thereof.In preferred embodiments, the phrase “does not degrade to anunacceptable extent” means that the active pharmaceutically acceptablecannabinoid ingredient (e.g., dronabinol) contained within the dosageform is maintained preferably between 90-110% of its initial(incorporated) amount during the desired (e.g., labeled) shelf-life ofthe dosage form (e.g., a minimum of 2 years after the date ofmanufacture of the dosage form).

For purposes of the invention, the term “dispersed” as it is used todescribe the presence of the cannabinoid in the oil-based carrier, ismeant to encompass a mixture of the cannabinoid and oil-based carrier inwhich the cannabinoid is completely or partially dissolved therein, orthe cannabinoid is partially or completely in solid particulate formtherein.

For purposes of the invention, the term “unacceptable degradation” meansdegradation of the cannabinoid within the dosage form to an extent whichwill cause the dosage form to have cannabinoid in the dosage form at alevel outside the acceptable ranges set forth herein, and/or which causethe formulation to include cannabinoid degradants at levels which exceedthe amounts specified herein, and/or which cause the formulation to notmeet its label claim for shelf life. In certain preferred embodiments,the cannabinoid formulations of the invention are deemed stable as perthe FDA guidance for two-year expiration dating.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a chromatogram of a formulation of 3.03% w/w dronabinol insesame oil after storage for two weeks at 55° C.

FIG. 2 is a chromatogram of a formulation of 3.03% w/w dronabinol insesame oil spiked with 1% w/w sesamin after storage for two weeks at 55°C.

DETAILED DESCRIPTION

It has been reported that because lipophilic compounds (e.g., such asdronabinol) are highly soluble in glycerol, these compounds migrate intothe shell of a soft gelatin capsule, thus inducing instability(Armstrong et al., 1984). The relatively large amount of glycerolpresent in soft gelatin has been reported to lead to increasedpermeability of the gelatin shell to oxygen (Cade et al., 1987; Hom etal., 1975). It is also known that Dronabinol readily degrades tocannabinol and cannabidiol in the presence of oxygen (Mechoulam, 1981).Also, the large amount of glycerol in soft gelatin has been reported tolead to increased sensitivity of formulation to heat and humidity(Bauer, 1983). Dronabinol has been reported to rapidly degrade todelta-8-tetrahydrocannabinol when exposed to heat (Mechoulam, 1981).Dronabinol is also believed to rapidly degrade when exposed to humidityor high moisture conditions. Glycerin or glycerol is a major componentin the gelatin shell that comprises the soft gelatin capsule. Glycerinfunctions as a plasticizer in soft gelatin and is therefore vital to themanufacture of soft gelatin capsules. Glycerin makes up approximately30% of the soft gelatin capsule shell (Ewart T. Cole, 2002).

As demonstrated in the appended examples, dronabinol is highly unstablein the presence of glycerin. In fact, as demonstrated in the appendedexamples, over one-third of the active ingredient dronabinol is lost todegradation in two weeks at 55° C. when exposed to even small quantitiesof glycerin (0.002%). In view of the known properties of soft gelatincapsules, it is believed that the manufacturing process of soft gelatincapsules may contribute to the degradation of moisture and glycerolsensitive compounds like dronabinol. In the hard gelatin capsuleprocess, the capsule is pre-fabricated and supplied empty whereas in thesoft gelatin capsule process the encapsulation and filling of drugformulation take place simultaneously. The moisture content ofgelatin/plasticizer mass at the filling stage can be around 50%, theequilibrium moisture level only being reached after several days ofstorage on trays. It is conceivable that during this most criticalperiod migration and degradation of moisture sensitive drugs likedronabinol, which are readily soluble in glycerol can occur. The brandeddronabinol product (Marinol, which consists of drug in sesame oilencapsulated in soft gelatin capsules) contains a significant amount ofglycerol in the soft gelatin shell and is therefore considered by theinventors of the present invention to inherently be an unstable drugproduct.

The instability of prior art dronabinol formulations has been overcomeby virtue of the present invention, which in certain embodiments (i)provides methods and formulations which eliminate the inclusion ofglycerin from the capsule shell of dronabinol formulations, e.g., viathe encapsulation of the dronabinol formulation into hard gelatincapsules; (ii) significantly reduces the possibility of the dronabinolformulation being exposed to moisture during storage; (iii) providesmethods and formulations which include anti-oxidants in effectiveamounts to substantially prevent or slow the oxidation of the dronabinolin the formulation such that, e.g., the formulation has a shelf-life ofat least two years; (iv) provides methods and formulations which includeorganic bases (amines) in effective amounts to stabilize the dronabinolin the formulation from degradation such that, e.g., the formulation hasa shelf-life of at least two years; or any combination of (i)-(iv)above.

Cannabinoids

Although certain sections of this specification provide specific focuson dronabinol, one skilled in the art will appreciate that the presentinvention is applicable to the class of pharmaceutically acceptablecannabinoids. For purposes of the present invention, the term“cannabinoid” includes naturally occurring and non-natural derivativesof cannabinoids which can be obtained by derivatization of naturalcannabinoids and which are unstable like natural cannabinoids. In otherwords, the cannabinoid used in the formulations of the invention may benatural, semi-synthetic, or synthetic. The cannabinoid may be includedin its free form, or in the form of a salt; an acid addition salt of anester; an amide; an enantiomer; an isomer; a tautomer; a prodrug; aderivative of an active agent of the present invention; differentisomeric forms (for example, enantiomers and diastereoisomers), both inpure form and in admixture, including racemic mixtures; enol forms. Theterm “cannabinoid” is also meant to encompass derivatives that areproduced from another compound of similar structure by the replacementof, e.g., substitution of one atom, molecule or group by another. Theterm “cannabinoid”, as used in the present invention, includes, interalia, delta-8-tetrahydrocannabinol, delta-9-tetrahydrocannabinol,cannabidol, olivetol, cannabinol, cannabigerol, nabilone,delta-9-tetrahydro cannabinotic acid, the non-psychotropic cannabinoid3-dimethylnepty 11 carboxylic acid homologine 8,delta-8-tetrahydrocannabinol. (J. Med. Chem. 35, 3135, 1992), prodrugsof cannabinoids, as well as pharmaceutically acceptable salts andcomplexes of cannabinoids. An example of a suitable prodrug isTHC-hemisuccinate.

The term “cannabinoid” is further meant to encompass naturalcannabinoids, natural cannabinoids that have been purified or modified,and synthetically derived cannabinoids, for example, U.S. PatentApplication Publication 2005/0266108, hereby incorporated by referencein its entirety, describes a method of purifying cannabinoids obtainedfrom plant material.

In certain preferred embodiments of the present invention, the activeingredient (cannabinoid) comprises or consists essentially ofDelta-9-tetrahydrocannabinol, also known as (and referred to herein as)dronabinol. Dronabinol is naturally-occurring and has been extractedfrom Cannabis saliva L. (marijuana). It has also been producedchemically as described in U.S. Pat. No. 3,668,224. Dronabinol is alight-yellow resinous oil that is sticky at room temperature, buthardens upon refrigeration. It turns to a flowable liquid when heated athigher temperatures. Dronabinol is insoluble in water and typicallyformulated in sesame oil. It has a pKa of 10.6 and an octanol-waterpartition coefficient: 6,000:1 at pH 7. Dronabinol is available innatural (extracted from plant) and synthetic forms. On the other hand,synthetic dronabinol may be utilized and may be synthesized using thestarting materials, Olivetol and p-2,8-menthadien-2-ol (PMD).

The term “dronabinol” is further meant to encompass naturally occurringdronabinol, synthetically derived dronabinol, and synthetically modifieddronabinol starting with a molecule obtained from a natural source forexample, U.S. Patent Application Publication 2005/0171361, herebyincorporated by reference in its entirety, describes a method ofextracting delta-9-THC acid from the plant material by chromatographyand then synthetically converting it to dronabinol.

The preparation of pharmaceutically acceptable cannabinoids useful inthe present invention may be accomplished via any procedure known tothose skilled in the art. Generally, in the isolation of THC and othercannabinoid constituents from the natural material (e.g., cannabis), thealcoholic or the petroleum ether or benzene or hexane extract of theplant is separated into neutral and acidic fractions, which are thenfurther purified by repeated column chromatography and/or countercurrentdistribution. Various adsorbents have been used in columnchromatography, especially silica gel, silicic acid, silicic acid-silvernitrate, florisil, acid washed alumina, and acid washed alumina-silvernitrate. U.S. Pat. Nos. 6,365,416 and 6,730,519 describe improvementswherein Cannabis plant material is extracted with a non-polar organicsolvent to provide an extract containing THC and the extract issubjected to fractional distillation under reduced pressure to provide adistillation fraction (distillate) having a high content of THC. Theprocess further comprises subjecting the extract from the plant materialto column chromatography prior to fractional distillation. A stillfurther aspect of the process comprises subjecting the distillate fromthe fractional distillation to column chromatography. Additionally, theprocess uses high pressure liquid chromatography (HPLC) in thepurification of the extract from the plant material. Another method ofmanufacture for obtaining cannabinoids useful in the present inventionincludes the method described in U.S. Pat. Nos. 6,730,519 and 6,365,416(both to Elsohly, et al.), both hereby incorporated by reference in itsentirety. Therein, a method for the isolation ofdelta-9-tetrahydrocannibinol (THC) from, Cannabis plant material isdescribed wherein delta-9-THC Acid and THC are separately obtainedincluding the steps of extracting the Cannabis plant material, chelatingdelta-9-THC acid on alumina solid support from cannabis extracts rich inthe acid washing of non-acid components of the extract with organicsolvents and eluting of the delta-9-THC acid with strong polar solvents.

In certain preferred embodiments of the invention, the cannabinoid usedin the formulation is esterified. Esterified forms of THC are describedin U.S. Pat. No. 4,933,368 and in U.S. Pat. No. 5,389,375. Other usefulpolar esters are the hemi-ester of malonic acid and the alaninate esterof alanine. It has been reported, e.g., in U.S. Pat. Nos. 5,508,051 and5,389,375, that salts of the terminal carboxylic acid group of theester, for example, the N-methyl glutamine salt as well as the sodiumand potassium salts are also useful. The descriptions of U.S. Pat. Nos.4,933,368; 5,508,037; and 5,389,375, are incorporated herein byreference. These ester compounds are hydrolyzed in the blood streamreleasing THC to provide a high degree of bioavailability of THC withoutregard to patient conditions and anomalies.

Oral THC is known to possess erratic absorption from thegastrointestinal tract, is subject to the first-pass effect resulting inheavy metabolism with production of high levels of 11-OH-THC, andundesirable side effects. The pro-drug THC hemisuccinate (THC-HS) hasbeen formulated in a suppository base as described in U.S. Pat. Nos.5,508,037 and 5,389,375, both of which are hereby incorporated byreference) in order to avoid this problem. Preliminary clinicalinvestigations show promise for this formulation (Mattes, R. D.; Shaw,L. M.; Edling-Owens, J., Engleman, K.; and ElSohly, M. A.; Bypassing thefirst-pass effect for the therapeutic use of cannabinoids; Pharm.,Biochem., Behav., 44(3):745-747, 1991; Mattes, R. D.; Engelman, K.;Shaw, L. M.; and ElSohly, M. A.; Bypassing the first-pass effect for thetherapeutic use of cannabinoids, Pharmacol., Biochem., Behav.,49(1):187-195, 1994; Brenneisen, R.; Egli, A.; ElSohly, M. A.; Henn, V.;and Speiss, Y.; The effect of orally and rectally administereddelta-9-tetrahydrocannabinol on spasticity: A pilot study with 2patients; Inter. J. Clin. Pharmacol. and Therapeutics, 34(10):446-452,1996; all of which are hereby incorporated by reference).

THC obtained by any means can be esterified by the reaction of THC withan organic acid, an organic acid halide or preferably organic acidanhydride in the presence of 4-amino-substituted pyridine alone or inadmixture with an organic amine, or in any other manner known to thoseskilled in the art. U.S. Pat. No. 6,008,383 (Elsohly, et al.), herebyincorporated by reference, describes a process for converting dronabinolto a variety of ester analogs, which process is said to be economicaland efficient. Therein, dronabinol is esterified by reaction with acarboxylic acid, an acid halide or an acid anhydride in the presence ofa 4-aminopyridine either alone or in admixture with an organic aminesuch as a mono-, di-, or tri-alkyl amine.

In certain preferred embodiments, the cannabinoid comprises dronabinolhemisuccinate ester (THC-HS).

Formulations

Cannabinoids in general, and dronabinol specifically, are insoluble inwater. The formulations of the present invention therefore preferablyinclude one or more pharmaceutically acceptable oil-based compounds,i.e., triglycerides, as a carrier for the cannabinoid. In certainembodiments, the oil-based compound or compounds are a liquid at roomtemperature. In certain other embodiments, the oil-based compound orcompounds are a semi-solid at room temperature.

Such oil-based compounds are readily available from commercial sources.Examples of suitable oil-based compounds include, but are not limitedto, Aceituno oil, Almond oil, Arachis oil, Babassu oil, Blackcurrantseed oil, Borage oil, Buffalo ground oil, Candlenut oil, Canola oil,Lipex 108 (Abitec), Castor oil, Chinese vegetable tallow oil, Cocoabutter, Coconut oil Pureco 76 (Abitec), Coffee seed oil, Corn oil,Cottonseed oil, Crambe oil, Cuphea species oil, Evening primrose oil,Grapeseed oil, Groundnut oil, Hemp seed oil, Illipe butter, Kapok seedoil, Linseed oil, Menhaden oil, Mowrah butter, Mustard seed oil,Oiticica oil, Olive oil, Palm oil, Palm kernel oil, Peanut oil, Poppyseed oil, Rapeseed oil, Rice bran oil, Safflower oil, Sal fat, Sesameoil, Shark liver oil, Shea nut oil, Soybean oil, Stillingia oil,Sunflower oil, Tall oil, Tea seed oil, Tobacco seed oil, Tung oil,(China wood oil), Ucuhuba, Vernonia oil, Wheat germ oil, mixtures of anyof the foregoing, and the like. Fractionated triglycerides, modifiedtriglycerides, synthetic triglycerides, and mixtures of triglyceridesare also within the scope of the invention.

Lecithin and Components of Lecithin as Carriers for Cannabinoids

In certain embodiments of the invention, lecithin may be used as part orall of the oil-based carrier. Cannabinoids are dispersible (dissolve) inlecithin. Lecithin is a complex mixture of phospholipids, glycolipids,triglycerides, sterols, small quantities of fatty acids, carbohydratesand sphingolipids. The primary phospholipid components of lecithin are:(i) phosphatidylcholine (13-18%); (ii) phosphatidylethonolamine(10-15%); (iii) phosphatidyinositol (10-15%) and (iv) phosphatidicacid(5-12%).

Experiments described herein showed that bases like ethanolamine preventdegradation of dronabinol. It is suggested that components of lecithin,(e.g., phosphatidyl ethanolamine and phosphatidyl choline) that containan amine functionality help protect dronabinol from degradation.Therefore, lecithin may include both anti-oxidant(s) and organic base(s)which impart stability to the cannabinoid. In addition to lecithin,commercially available phospholipids may also be suitable as oil-basedcarriers.

Exemplary phospholipids suitable for oral dosage forms include: Phosal®50 PG; Phosal® 53MCT; Phosal® 75SA, Phospholipon® 80; Phospholipon®80H;Phospholipon®85G; Phospholipon® 90G; Phospholipon® 90H; andPhospholipon® 90NG. Exemplary phospholipids suitable for dermal dosageforms include: Phosal® 50 PG; Phosal® 50SA;Phosal®53MCT; Phosal® 75SA;Phospholipon® 80; Phospholipon® 80H; Phospholipon® 85G; Phospholipon®90NG; Phospholipon®90G; Phospholipon® 90H; and Phospholipon® 100H.Exemplary phospholipids suitable for parenteral dosage forms include:Phospholipon®90G; Phospholipon®90H; and Phospholipon® 100H. Phosholipidssuitable for pulmonary drug formulations include: Phospholipon® 90G;Phospholipon® 9.0H and Phospholipon®.

Preferred triglycerides include vegetable oils, fish oils, animal fats,hydrogenated vegetable oils, partially hydrogenated vegetable oils,medium and long-chain triglycerides, and structured triglycerides.Preferred oils are vegetable oils such as soybean oil, olive oil, cottonseed oil, peanut oil, sesame oil and castor oil, with sesame oil andcastor oil being preferred. Vitamin E (tocopherol) can also be used asthe oil phase. This material is also an antioxidant and can help tostabilize the chosen cannabinoid (which as a class tend to be prone tooxidation).

In certain preferred embodiments, the oil-based carrier utilized in theformulations of the invention comprises sesame oil or cottonseed oil,most preferably sesame oil. The antioxidant properties of sesame oilhave previously been reported in literature (Kato et al., 1998). Sesameoil is a major component of Marinol capsules and comprises over 90% ofthe finished product. The antioxidant effect of sesame oil has beenattributed to the presence of several antioxidant chemicals in sesameoil. They include sesamin, sesamol, sesamolin and lecithin (BradleyMorris, 2002; Sirato-Yasumoto et al., 2001). It is preferred that thesesame oil used in the formulations of the present invention contain oneor more of these anti-oxidants.

In certain embodiments, the formulation contains from about 0.05 toabout 90% cannabinoid, weight to weight (w/w), with the remaindercomprising the oil-based carrier. In preferred embodiments, theformulation contains from about 0.1% to about 50% by weight, and incertain preferred embodiments from about 1.5 to about 6% cannabinoid, byweight, with the remainder comprising the oil-based carrier, and incertain preferred embodiments, the formulation contains from about 2.5%to about 4.5% cannabinoid by weight, with the remainder comprising theoil-based carrier.

In preferred embodiments, the cannabinoid formulations of the inventiondo not degrade to an unacceptable extent such that the final product(cannabinoid dosage form) has a shelf-life of at least about 2 years. Aspreviously mentioned, this means that the active ingredient (e.g.,dronabinol) within the dosage form remains within 90-110% of its initialamount in the dosage form during the desired (e.g., labeled) shelf-lifeof the dosage form (e.g., a minimum of 2 years after the date ofmanufacture of the dosage form). In further preferred embodiments, wherethe dosage form contains dronabinol as the active ingredient, the dosageform will contain not greater than 2% D8THC during the claimedshelf-life of the dosage form. In further preferred embodiments, wherethe dosage form contains dronabinol, the dosage form will contain notgreater than 2% cannabidiol during the claimed shelf-life of the dosageform. In further preferred embodiments, where the dosage form containsdronabinol, the dosage form will contain not greater than 1% exo-THC. Incertain especially preferred embodiments where the dosage form containsdronabinol as the active ingredient, the dosage form will contain thefollowing during its claimed shelf-life: (i) not less than 90% of theinitial dronabinol content; (ii) not greater than about 2% cannabinol;(iii) not greater than about 2% delta-8-THC; (iv) not greater than 2%cannabidiol; (v) not greater than about 0.5% exo-THC; or any combinationof the foregoing. Although exo-THC is not a degradant of dronabinol, itis an impurity formed during the synthesis of dronabinol. These rangesof particular degradants/impurities may be applicable for othercannabinoids, as well.

Hard Gelatin Capsules

In one embodiment, the present invention overcomes the deficiencies ofprior art dronabinol oral dosage forms via the utilization of hardgelatin capsules in replacement of the soft gelatin capsules of theprior art. Hard gelatin capsules suitable for liquid filling areidentical in composition to hard gelatin capsules used for powders. Incontrast to soft gelatin capsule shells, hard gelatin capsule shells donot contain glycerol, and therefore a major cause of instability for theactive pharmaceutical ingredient is eliminated. Hard gelatin capsuleshells also have a lower moisture content than soft gelatin capsules.The moisture uptake for soft gelatin capsules plasticized with glycerolis considerably higher than that for hard gelatin capsules [Bauer K H,“Die Herstellung von Hart—und Weichgelatinekapseln.” In Die Kapsel. WFahrig and U H Hofer, Eds., Wissenschaftliche Verlags GmbH, Stuttgart,pp. 58-82 (1983)] Therefore, it is believed that the hard gelatincapsule shells used in embodiments of the present invention will havelower moisture content compared to soft gelatin shells. It has beenreported that liquid and semi-solid formulations in hard gelatincapsules may improve bioavailability and stability for moisture oroxygen-sensitive drugs (Shah, et al., 2003). Also, by utilizing hardgelatin capsules to encapsulate the cannabinoid (e.g., dronabinol)solution, the need for the plasticizer glycerin is eliminated.

Alternatively, the cannabinoid solutions in oil-based carriers can beincorporated into a soft gelatin capsule, a cellulosic capsule, a starchcapsule, and a non-gelatin capsule shell, in any manner known to thoseskilled in the art. Exemplary non-gelatin capsule shells includehydrocolloid film-forming compositions as described in U.S. Pat. No.6,949,256, hereby incorporated by reference. As described in U.S. Pat.No. 6, 949,256, non-animal based (e.g., non-glycerin containing)compositions may be used to encapsulate oil-based compositions such asthose of the present invention. Such non-animal based compositions aredescribed therein as comprising iota carrageenan in an amount from about1-15%; kappa carrageenan in an amount less than or equal to 50% byweight of the total encapsulation (film-forming) composition; a bulkingagent in the ratio of bulking agent:total carrageenan from at leastabout 1:1 to about 20:1; a plasticizer in an amount from about 10-50%,and water to form 100% by weight of the composition. The kappacarrageenan provides gel strength while the iota carrageenan providesflexibility to the composition. A mixture of kappa carrageenan and aglucomannan such as konjac flour may be used in place of some or all ofthe kappa karageenan in the composition, as described in U.S. Pat. No.6,949,256. Furthermore, one skilled in the art will appreciate that itwould be possible to substitute other naturally occurring or syntheticgums used in pharmaceuticals and/or food products to achieve similarresults. The bulking agent may be, e.g., a modified starch. A usefulplasticizer may be, e.g., a combination of sorbitol and maltitol.Briefly, and as discussed in detail in U.S. Pat. No. 6, 949,256,capsules utilizing such compositions may be prepared by using a rotarydie process in which a molten mass of the composition is fed onto cooleddrums to form two spaced sheets or ribbons in a semi-molten state. Thesesheets are fed around rollers and brought together a convergent angleinto the nip of a pair of roller dies that include opposed die cavities.A dosage form (e.g., the cannabinoid dispersed in oil-based carrier) isfed into the wedge-shaped joinder of the sheets such that it is trappedbetween the sheets inside the die cavities. The sheets are then pressedtogether and cut in a manner to encapsulate the enclosed formulation.

Alternatively, the cannabinoid solutions in oil-based carriers can beincorporated into a non-reactive container (e.g., a glass vial), in anymanner known to those skilled in the art.

It is believed that the cannabinoid formulations encapsulated withinhard gelatin capsules in accordance with the present invention aresignificantly more stable than formulations contained withincommercially available soft gelatin capsules (e.g. Marinol). A possibleexplanation is that the higher moisture content of soft gelatin capsuleshells combined with glycerol induces migration of the active ingredientdronabinol, leading to its profound instability (e.g., in the currentlyavailable commercialized dronabinol product). Therefore, a major causeof instability of the active pharmaceutical ingredient dronabinol may beeliminated by encapsulating the formulation in hard gelatin capsules.The stability studies set forth in the appended examples are believed toconfirm that by utilizing hard gelatin capsules to encapsulate thecannabinoid solution and eliminating the inclusion of glycerin/glycerol,an oral cannabinoid drug product that is stable for at least about twoyears at room temperature is obtained.

Table 1 provides examples of cannabinoid formulations in accordance withthe present invention. As can be ascertained from that table, hardgelatin capsules contain from about 85% to about 100% gelatin and fromabout 1% to about 15% water. TABLE 1 Examples of Formulation CompositionCONCENTRATION COMPONENT RANGE (W/W) Dronabinol 1.5-6.0%; 0.05-90% SesameOil  0-100% Sesamin 0-10% Sesamol 0-10% Sesamolin 0-10% Lecithin 0-10%Capsule Shell Gelatin 85-100% Water 1-15%

Hard gelatin capsules have been used for many years in the oral deliveryof pharmaceutical compounds. Drug formulations in a powdered or granularform are usually filled into a hard gelatin capsule thus providing for aunit dose that effectively masks the bitter taste of some drugs. Morerecently, new technology has been developed to accurately dose and sealliquids into hard gelatin capsules (Shah et al., 2003).

To prepare liquid filled hard gelatin capsules, basically the hardgelatin capsules are filled with the (compatible) drug/carrier, and thenthe capsule is sealed, e.g., by spraying a small amount of water/ethanolmixture at the cap and body interface followed by a gentle warming(optional) to fuse the two capsule parts together.

In further embodiments, additional excipients compatible with hardgelatin capsule shells may be incorporated into the liquid drugformulation, if needed, such as known viscosity modifiers for lipophilicliquid vehicles (e.g., Aerosil, Cetostearyl alcohol, Gelucires 33/01,39/01 and 43/01, glyceryl behenate, glyceryl palmitostearate, Softisans100, 142, 378 and 649, and stearyl alcohol; and solubilizing agents(surfactants) such as Capryol 90, Gelucire 44/14, 50/13, Cremophor RH40, Imitor 191.308, 742,780 K, 928 and 988, Labrafil M 1994 CS, M 2125CS, Lauroglycol 90, PEG MW >4000, Plurol Oleique CC 497, Poloxamer 124and 188, Softigen 701, 767, Tagat TO, and Tween 80.

Stabilizers

In certain preferred embodiments, the oil-based carrier contains amountsof one or more pharmaceutically acceptable anti-oxidants in an amounteffective to stabilize the cannabinoid contained therein such that thecannabinoid does not degrade to an unacceptable extent and theformulation is deemed stable as per the FDA guidance for two-yearexpiration dating (i) when placed under accelerated storage conditionsof elevated temperature and humidity of 40° C./75% relative humidity(RH) for 6 months, and/or (ii) when placed under elevated temperatureconditions of 55° C. for two weeks; and/or when stored at roomtemperature (25° C.) for two years.

In certain preferred embodiments, the oil-based carrier is sesame oiland the formulation contains one or more anti-oxidants (e.g., sesamin,sesamol, sesamolin, lecithin, and any combinations thereof) in an amounteffective to stabilize the cannabinoid contained therein (e.g.,dronabinol). It is noted that although lecithin is generally recognizedas an emollient, emulsifier, and solubilizer, it was observed thatlecithin protects cannabinoids much like an anti-oxidant. Lecithin isalso referred to as an anti-oxidant in the literature (e.g., FeaturedExcipient: Antioxidants, 1999 and Bradley Morris, 2002; Sirato-Yasumotoet al., 2001).

In certain preferred embodiments, the formulation contains a total ofabout 0.001% to about 50% of an anti-oxidant(s) selected from sesamin,sesamol, sesamolin, lecithin, and any combinations thereof. In certainother preferred embodiments, the oil-based carrier in the formulationcomprises from about 0.001% to about 10% of an anti-oxidant(s) selectedfrom sesamin, sesamol, sesamolin, lecithin, and any combinationsthereof. In other preferred embodiments, the oil-based carrier in theformulation comprises from about 0.01% to about 10% of ananti-oxidant(s) selected from sesamin, sesamol, sesamolin, lecithin, andany combinations thereof.

In other embodiments of the invention, the oil-based carrier does notinherently contain an anti-oxidant such as sesamin, sesamol, sesamolin,or lecithin, and in certain preferred embodiments effective amounts ofone or more of these anti-oxidants is added to the formulation in orderto stabilize the cannabinoid contained therein.

In further embodiments of the invention, an effective (stabilizing)amount of one or more pharmaceutically acceptable anti-oxidants is addedto the oil-based carrier. The term “anti-oxidant” is used herein todescribe any compound which is oxidized more easily than the cannabinoidcompounds included in the dosage forms of the present invention. Any ofthe known anti-oxidants may be used, including but not limited toanti-oxidants such as butyl hydroxyl anisole (BHA), butyl hydroxyltoluene (BHT), propyl gallate, lecithin, Vitamin E tocopherol, sesamin,sesamol, sesamolin, alpha tocopherol, ascorbic acid, ascorbyl palmitate,fumaric acid, malic acid, sodium ascorbate and sodium metabisulphite, aswell as chelating agents such as disodium EDTA, may also be used tostabilize the cannabinoid formulations of the present invention.

The preparation may also contain anti-oxidant synergists to preventoxidative degradation. Any of the known anti-oxidant synergists may alsobe used in effective amounts, for example disodium edetate.

The level of anti-oxidant which may be used will be optimized for eachformulation, in order to obtain a stable product (dosage form) havingthe desired shelf-life. Generally speaking, in embodiments in which ananti-oxidant is included, suitable formulations may include from about0.001% to about 50% w/w of a pharmaceutically acceptableanti-oxidant(s). For example, in certain preferred embodiments, theamount of lecithin included in the cannabinoid dosage form is in therange from about 0.1 to about 10% w/w, and in certain embodiments morepreferably from about 0.3% to about 8.25% w/w. In other preferredembodiments, the amount of L-ascorbic acid-6-palmitate is from about0.001 to about 1%, w/w, and in certain embodiments more preferably inthe range from about 0.01%-to about 0.1% w/w. The anti-oxidantpreferably prevents the formation of degradants in the dosage form suchas those mentioned above, namely delta-8 tetrahydrocannabinol (D8THC),cannabinol (CBN), or cannabidiol (CBD), to unacceptable levels (e.g., aspreviously specified herein).

In certain other embodiments, the formulation contains one or more ofthe following stabilizers, lysolecithin; phosphatidylcholine;phosphatidylethanolamine; phosphatidylglycerol; phosphatidic acid;phosphatidylserine; lysophosphatidylcholine;Iysophosphatidylethanolamine; lysophosphatidylglycerol; lysophosphatidicacid; lysophosphatidylserine; PEG-phosphatidylethanolamine;PVP-phosphatidylethanolamine; mixtures thereof; and mixtures of any ofthe foregoing with lecithin.

Organic Bases

In further embodiments of the invention, effective amounts of one ormore pharmaceutically acceptable organic bases are added to thecannabinoid and oil-based carrier mixture in order to stabilize thecannabinoid from undesirable levels of degradation. In certain preferredembodiments, the oil-based carrier contains amounts of one or morepharmaceutically acceptable organic bases in an amount effective tostabilize the cannabinoid contained therein such that the cannabinoiddoes not degrade to an unacceptable extent and the formulation is deemedstable as per the FDA guidance for two-year expiration dating (i) whenplaced under accelerated storage conditions of elevated temperature andhumidity of 40° C./75% relative humidity (RH) for 6 months, and/or (ii)when placed under elevated temperature conditions of 55° C. for twoweeks; and/or when stored at room temperature (25° C.) for two years.

Examples of suitable organic bases which may be effectively used in thecannabinoid formulations of the present invention include but are notlimited to any pharmaceutically acceptable primary organic amines whichare GRAS ingredients (generally regarded as safe), such asmethanolamine, ethanolamine, meglumine, other alkylamines (e.g. di-alkylamines and tri-alkyl amines), and any combination thereof

In certain preferred embodiments, the amount of organic base(s) in thecannabinoid/oil-based carrier mixture is from about 0.001% w/w to about5% w/w, and more preferably from about 0.007% w/w to about 2% w/w.

In other preferred embodiments, the cannabinoid/oil-based carriermixtures include stabilizing amounts of both one or more anti-oxidantsand one or more organic bases.

In further alternative embodiments, the cannabinoid solutions inoil-based carriers can be incorporated into soft gelatin capsules, wheresufficient amounts of anti-oxidant(s), organic base(s), or combinationsthereof are included therein in order to provide a room temperaturestable soft gelatin cannabinoid capsule in accordance with the presentinvention. In certain preferred embodiments, the cannabinoid isdronabinol.

Soft Gelatin Capsules

In certain embodiments, the liquid formulations of the present invention(e.g., cannabinoid in oil-based carrier) can be stabilized utilizingeffective amounts of (i) an anti-oxidant(s); (ii) an organic base; or(iii) a combination of an anti-oxidant and an organic base, such thatthe liquid formulation can be encapsulated within a soft gelatin capsuleand remain stable for a desired period of time (e.g., such that thecannabinoid does not degrade to an unacceptable extent and theformulation is deemed stable as per the FDA guidance for two-yearexpiration dating (i) when placed under accelerated storage conditionsof elevated temperature and humidity of 40° C./75% relative humidity(RH) for 6 months, and/or (ii) when placed under elevated temperatureconditions of 55° C. for two weeks; and/or when stored at roomtemperature (25° C.) for two years).

Additional Ingredients

Formulations of the invention also may include one or more additionalexcipients incorporated into the formulation, if needed. Exemplaryexcipients are:

Viscosity modifiers for lipophilic vehicles (e.g., Aerosil, Cetostearylalchohol, Cetyl alcohol, stearyl alcohol, Gelucires 33/01, 39/01 and43/01, glyceryl behenate, glyceryl palmitostearate, Softisans 100, 142,378 and 649, and stearyl alcohol;

Solubilizin2 agents (e.g., Capryol 90; Cremophor RH40; Labrafil M 1944CS; Labrafil M 2125 CS; Lauroglycol 90; PEG MW>4000; Plurol Oleique CC497; poloxamer 124; poloxamer 188; Softigen 701; Softigen 767; Tagat TO;Tween 80; triacetin; triethylcitrate; tributylcitrate; acetyltriethylcitrate; acetyl tributyl citrate; triethylcitrate; ethyl oleate;ethyl caprylate; ethyl butyrate; triacetin; 2-pyrrolidone; 2-piperidone;N-methylpyrrolidone; N-ethylpyrrolidone; N-hydroxyethyl pyrrolidone;N-octylpyrrolidone; N-laurylpyrrolidone; dimethylacetamide; and mixturesthereof);

Surfactants (e.g. Capryol 90; Cremophor RH40; Gelucire 44/14; Gelucire50/13; Imwitor 91; Imwitor 308; Imwitor 380; Imwitor 742; Imwitor 780K;Imwitor 928; Imwitor 988; Labrafil M 1944 CS; Labrafil M 2125 CS;Lauroglycol 90; Tagat TO; Tween 80; and mixtures thereof); emulsifiers(e.g., Gelucire 44/14; Gelucire 50/13; Imwitor 91; Imwitor 308; Imwitor380; Imwitor 742; Imwitor 780K; Imwitor 928; Imwitor 988; poloxamer 124;poloxamer 188; Tagat TO; Tween 80; lecithin; lysolecithin;phosphatidylcholine; phosphatidylethanolamine; phosphatidylglycerol;phosphatidic acid; phosphatidylserine; lysophosphatidylcholine;Iysophosphatidylethanolamine; lysophosphatidylglycerol; lysophosphatidicacid; lysophosphatidylserine; PEG-phosphatidylethanolamine;PVP-phosphatidylethanolamine; and mixtures thereof); and

Absorption enhancers (e.g., Gelucire 44/14; Gelucire 50/13; Tagat TO;Tween 80; and mixtures thereof).

It is recognized that pharmaceutical excipients may perform more thanone function, and are therefore characterized as having different usesdepending on the particular application. While the use of an excipientin the context of a particular formulation may determine the function ofthe excipient, the inclusion of any particular excipient into any one ormore category as set forth above is not meant to limit the function ofthat excipient.

Seal Coating

In accordance with the invention, the dosage form may further be coatedwith a seal coating alone or in addition to another coating. In oneembodiment, the seal coating occurs between the core and the entericcoating. The seal coating may comprise a hydrophilic polymer. Examplesinclude but are not limited to hydroxypropylcellulose,hydroxypropylmethylcellulose, methoxypropyl cellulose,hydroxypropylisopropylcellulose, hydroxypropylpentylcellulose,hydroxypropylhexylcellulose and any mixtures thereof. The seal coat mayalso be a polymer such as polyvinyl alcohol.

The seal coating may be applied by press coating, molding, spraying,dipping and/or air-suspension or air tumbling procedures. A preferredmethod of applying the seal coating is by pan coating, where the sealcoating is applied by spraying it onto the cores accompanied by tumblingin a rotating pan. The seal coating material may be applied to thedosage form as a suspension by employing solvents, e.g., an organic,aqueous, or a mixture of an organic and aqueous solvent. The sealcoating material and solvent should be compatible with the encapsulatingmaterial of the dosage form, active pharmaceutical ingredient(s), andany other coating. Exemplary solvents suitable in applying the sealcoating include aqueous-based solutions, an alcohol, ketone, ester,ether, aliphatic hydrocarbon, halogenated solvents, cycloaliphaticsolvents, aromatic, heterocyclic, aqueous solvents, and mixturesthereof. In a preferred embodiment, the seal coating compriseshydroxypropyl cellulose and hydroxypropylmethylcellulose, and isdelivered as a suspension using a suitable solvent such as e.g., ethanolor water.

Enteric Coating

The dosage form of the present invention may also be coated with anenteric layer, alone or in addition to another coating. The entericmaterials for use in the enteric layer preferably resist the action ofgastric fluid preferably allowing for release of the active agent in theintestinal tract.

Suitable enteric coating may comprise cellulose acetate phthalate,polyvinyl acetate phthalate, acrylic resins such as Eudragit L(g.,shellac, cellulose acetate butyrate, hydroxypropyl methylcellulosephthalate or combinations thereof.

Additional materials suitable for use in the enteric coating includephthalates including cellulose acetyl phthalate, cellulose triacetylphthalate, cellulose acetate tetrahydrophthalate, cellulose acetatetrimellilate, sodium cellulose acetate phthalate, cellulose esterphthalate, cellulose ether phthalate, methylcellulose phthalate,cellulose ester-ether phthalate, hydroxy propyl cellulose phthalate,alkali salts of cellulose acetate phthalate, alkaline earth salts ofcellulose acetate phthalate, calcium salt of cellulose acetatephthalate, ammonium salt of hydroxypropyl methylcellulose phthalate,cellulose acetate hexahydrophthalate, hydroxypropyl methylcellulosehexahydrophthalate, and polyvinyl acetate phthalate, may be used asgastroresistant, enterosoluble coatings for the formulations of thepresent invention. Other enteric coatings may be used as long as they donot readily dissolve or disperse in the gastric juices of the stomachbut do dissolve or disperse in the intestinal fluid of the intestines.An acrylic-based film-coating system, commercially available asAcryl-EZE® by Colorcon, West Point, Va, is a preferred enteric coating.Enteric materials are also particularly preferred because they form animpermeable barrier which will not readily dissolve or disperse at thelow pH provided by the gastric juices in the stomach. The entericmaterials are discussed in Remington's Pharmaceutical Sciences, 17thEd., page 1637 (1985).

The enteric coating may be applied by press coating, molding, spraying,dipping and/or air-suspension or air tumbling procedures. One method ofapplying the enteric coating is by pan coating, where the entericcoating is applied by spraying the enteric composition onto the coresaccompanied by tumbling in a rotating pan. The enteric coating materialmay be applied to the cores by employing solvents, including an organic,aqueous or a mixture of an organic and aqueous solvent. The entericcoating material and solvent should be compatible with the encapsulatingmaterial of the dosage form, active pharmaceutical ingredient(s), andany other coating. Exemplary solvents suitable in applying the entericcoating include an alcohol, ketone, ester, ether, aliphatic hydrocarbon,halogenated solvents, cycloaliphatic solvents, aromatic, heterocyclic,aqueous solvents, and mixtures thereof.

Controlled Release Coating

In other embodiments of the invention the formulation is coated with acontrolled release coating, which is compatible with the othercomponents of the dosage form. The controlled release coating maycomprise a hydrophobic controlled release material selected from (i) analkylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof. Thecoating may be applied in the form of an organic or aqueous solution ordispersion.

In certain embodiments, the controlled release coatings include aplasticizer such as those described herein.

In certain embodiments, it is necessary to overcoat the substratecomprising the active pharmaceutical ingredient with an aqueousdispersion of e.g., alkylcellulose or acrylic polymer to obtain acontrolled-release formulation. The amount of overcoat may varydepending upon the physical properties of the active pharmaceuticalingredient and the desired release rate, the inclusion of plasticizer inthe aqueous dispersion and the manner of incorporation of the same, forexample.

Alkylcellulose Polymers

Cellulosic materials and polymers, including alkylcelluloses arecontrolled release materials suited for coating substrates containingthe active pharmaceutical ingredient according to the invention. Simplyby way of example, one preferred alkylcellulosic polymer isethylcellulose, although the artisan will appreciate that othercellulose and/or alkylcellulose polymers may be readily employed, singlyor on any combination, as all or part of a hydrophobic coatingsaccording to the invention.

One commercially-available aqueous dispersion of ethylcellulose isAquacoatg (FMC Corp., Philadelphia, Pa., U.S.A.). Aquacoat® is preparedby dissolving the ethylcellulose in a water-immiscible organic solventand then emulsifying the same in water in the presence of a surfactantand a stabilizer. After homogenization to generate submicron droplets,the organic solvent is evaporated under vacuum to form a pseudolatex.The plasticizer is not incorporated in the pseudolatex during themanufacturing phase. Thus, prior to using the same as a coating, it isnecessary to intimately mix the Aquacoat® with a suitable plasticizerprior to use.

Another aqueous dispersion of ethylcellulose is commercially availableas Surelease® (Colorcon, Inc., West Point, Pa., U.S.A.). This product isprepared by incorporating plasticizer into the dispersion during themanufacturing process. A hot melt of a polymer, plasticizer (dibutylsebacate), and stabilizer (oleic acid) is prepared as a homogeneousmixture, which is then diluted with an alkaline solution to obtain anaqueous dispersion which can be applied directly onto substrates.

Acrylic Polymers

In other preferred embodiments of the present invention, the controlledrelease material comprises a pharmaceutically acceptable acrylicpolymer, including but not limited to acrylic acid and methacrylic acidcopolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates,cynaoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid),methacrylic acid alkylamide copolymer, poly(methyl methacrylate),polymethacrylate, poly(methyl methacrylate)copolymer, polyacrylamide,aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers.

In certain preferred embodiments, the acrylic polymer is comprised ofone or more ammonio methacrylate copolymers. Ammonio methacrylatecopolymers are well known in the art, and are described in NF XVII asfully polymerized copolymers of acrylic and methacrylic acid esters witha low content of quaternary ammonium groups.

In order to obtain a desirable dissolution profile, it may be necessaryto incorporate two or more ammonio methacrylate copolymers havingdiffering physical properties, such as different molar ratios of thequaternary ammonium groups to the neutral (meth)acrylic esters.

Certain methacrylic acid ester-type polymers are useful for preparingpH-dependent coatings which may be used in accordance with the presentinvention. For example, there are a family of copolymers synthesizedfrom diethylaminoethyl methacrylate and other neutral methacrylicesters, also known as methacrylic acid copolymer or polymericmethacrylates, commercially available as Eudragit® from Röhm Tech, Inc.There are several different types of Eudragit®. For example, Eudragit Eis an example of a methacrylic acid copolymer which swells and dissolvesin acidic media. Eudragit L is a methacrylic acid copolymer which doesnot swell at about pH<5.7 and is soluble at about pH>6. Eudragit S doesnot swell at about pH<6.5 and is soluble at about pH>7. Eudragit RL andEudragit RS are water swellable, and the amount of water absorbed bythese polymers is pH-dependent, however, dosage forms coated withEudragit RL and RS are pH-independent.

In certain preferred embodiments, the acrylic coating comprises amixture of two acrylic resin lacquers commercially available from RohmPharma under the Tradenames Eudragit® RL30D and Eudragit® RS30D,respectively. Eudragit® RL30D and Eudragit® RS30D are copolymers ofacrylic and methacrylic esters with a low content of quaternary ammoniumgroups, the molar ratio of ammonium groups to the remaining neutral(meth)acrylic esters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit®RS30D. The mean molecular weight is about 150,000. The code designationsRL (high permeability) and RS (low permeability) refer to thepermeability properties of these agents. Eudragit® RL/RS mixtures areinsoluble in water and in digestive fluids. However, coatings formedfrom the same are swellable and permeable in aqueous solutions anddigestive fluids.

The Eudragit® RL/RS dispersions of the present invention may be mixedtogether in any desired ratio in order to ultimately obtain acontrolled-release formulation having a desirable dissolution profile.Desirable controlled-release formulations may be obtained, for instance,from a retardant coating derived from 100% Eudragit® RL, 50% Eudragit®RL and 50% Eudragit® RS, and 10% Eudragit® RL:Eudragit® 90% RS. Ofcourse, one skilled in the art will recognize that other acrylicpolymers may also be used, such as, for example, Eudragit® L.

Plasticizers in Control Release Coatings

In embodiments of the present invention where the coating comprises anaqueous dispersion of a hydrophobic controlled release material, theinclusion of an effective amount of a plasticizer in the aqueousdispersion of hydrophobic material will further improve the physicalproperties of the controlled-release coating. For example, becauseethylcellulose has a relatively high glass transition temperature anddoes not form flexible films under normal coating conditions, it ispreferable to incorporate a plasticizer into an ethylcellulose coatingcontaining controlled-release coating before using the same as a coatingmaterial. Generally, the amount of plasticizer included in a coatingsolution is based on the concentration of the film-former, e.g., mostoften from about 1 to about 50 percent by weight of the film-former.Concentration of the plasticizer, however, can only be properlydetermined after careful experimentation with the particular coatingsolution and method of application.

Examples of suitable plasticizers for ethylcellulose include waterinsoluble plasticizers such as dibutyl sebacate, diethyl phthalate,triethyl citrate, tibutyl citrate, and triacetin, although it ispossible that other water-insoluble plasticizers (such as acetylatedmonoglycerides, phthalate esters, castor oil, etc.) may be used.Triethyl citrate is an especially preferred plasticizer for the aqueousdispersions of ethyl cellulose of the present invention.

Examples of suitable plasticizers for the acrylic polymers of thepresent invention include, but are not limited to citric acid esterssuch as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate,and possibly 1,2-propylene glycol. Other plasticizers which have provedto be suitable for enhancing the elasticity of the films formed fromacrylic films such as Eudragit® RL/RS lacquer solutions includepolyethylene glycols, propylene glycol, diethyl phthalate, castor oil,and triacetin. Triethyl citrate is an especially preferred plasticizerfor the aqueous dispersions of ethyl cellulose of the present invention.

In certain embodiments, the addition of a small amount of talc to thecontrolled release coating reduces the tendency of the aqueousdispersion to stick during processing, and acts as a polishing agent.

Additional Drugs

Cannabinoids such as dronabinol may be used alone or in combination withother medications. Those skilled in the art will readily recognize that,for example, in the case of AIDS wasting syndrome, the patient willlikely also be taking drugs that combat the AIDS virus. Similarly, thoseskilled in the art will readily recognize that patients receivingchemotherapy for cancer may also receive other antiemetics, and cancerpatients seeking to relieve pain are likely to receive opioids as wellas nonsteroidal anti-inflammatory agents. The formulations and methodsof the invention may further include one or more additionaltherapeutically active agents, such as, for example, non-narcoticanalgesics such as acetaminophen or aspirin, opioid or opiateanalgesics, non-steroidal anti-inflammatory drugs (NSAIDs, for example,non-selective cyclooxygenase inhibitors and COX-2 inhibitors),anti-emetics (for example, ondansetron) and steroids (for examplemegestrol acetate, oxandrolone, oxymetholone). In certain embodiments ofthe invention, a second therapeutically active drug including but notlimited to the above-mentioned drugs, is incorporated into the oralcannabinoid dosage form. In yet other embodiments, the secondtherapeutically active drug is separately administered to the patient inconjunction with the oral cannabinoid dosage form. The sequence in whichthe therapeutic agents are administered is not narrowly critical.“Combination therapy” embraces the administration of the therapeuticagents as described above in further combination with other biologicallyactive ingredients, such as, but not limited to, a pain reliever, suchas a steroidal or nonsteroidal anti-inflammatory drug, or an agent forimproving stomach motility, for example, and with non-drug therapies,such as, but not limited to, surgery.

The therapeutic compounds that make up the combination therapy may alsobe administered sequentially, with either therapeutic compound beingadministered by a regimen calling for two-step administration. Thus, aregimen may call for sequential administration of the therapeuticcompounds with spaced-apart administration of the separate, activeagents. The time period between the multiple administration steps mayrange from, for example, a few minutes to several hours to days,depending upon the properties of each therapeutic compound such aspotency, solubility, bioavailability, plasma half-life and kineticprofile of the therapeutic compound, as well as depending upon theeffect of food ingestion and the age and condition of the subject.Circadian variation of the target molecule concentration may alsodetermine the optimal dose interval.

The therapeutic compounds of the combined therapy whether administeredsimultaneously, substantially simultaneously, or sequentially, mayinvolve a regimen calling for administration of one therapeutic compoundby oral route and another therapeutic compound by an oral route, apercutaneous route, an intravenous route, an intramuscular route, or bydirect absorption through mucous membrane tissues, for example. Whetherthe therapeutic compounds of the combined therapy are administeredorally, rectally, topically, buccally, sublingually, or parenterally(for example, subcutaneous, intramuscular, intravenous and intradermalinjections, or infusion techniques), separately or together, each suchtherapeutic compound will be contained in a suitable pharmaceuticalformulation of pharmaceutically-acceptable excipients, diluents or otherformulations components.

Other additives conventionally used in pharmaceutical compositions canbe included, and these additives are well known in the art. Suchadditives include pharmaceutically acceptable detackifiers, anti-foamingagents, buffering agents, antioxidants, preservatives, chelating agents,viscomodulators, tonicifiers, flavorants, colorants odorants,opacifiers, suspending agents, binders, fillers, plasticizers,lubricants, and mixtures thereof. The amounts of such additives can bereadily determined by one skilled in the art, according to theparticular properties desired, keeping in mind the possibility that anysuch additives should preferably not negatively impact the stability ofthe final formulation.

Route of Administration

The formulations of the present invention are preferably administeredorally. However, one skilled in the art will appreciate that thestabilized cannabinoid formulations of the present invention are notlimited to administration by the oral route, and can be administered viathe nasogastric route, a percutaneous route, an intravenous route, anintramuscular route, or by direct absorption through mucous membranetissues (e.g., buccally or rectally). Although formulations specificallysuited to oral administration are presently preferred, the compositionsof the present invention can also be formulated for topical,transdermal, buccal, ocular, pulmonary, vaginal, rectal, transmucosal orparenteral administration, as well as for oral administration. Thus, thedosage form can be a solution, suspension, emulsion, suppository, spray,aerosol, gel, drops, syrup, elixir, or other dosage form, as desired.

Dosage

The dosage range of dronabinol may vary widely from 2.5 mg to 20 mgdaily, in single or divided doses, or therapeutically equivalent amountsof one or more other cannabinoids may be utilized (as can be determinedby one skilled in the art).

Making the Capsule

In one embodiment of the invention, the cannabinoid formulation is aliquid-filled hard capsule. An essential part of a liquid-fillingoperation is the ability to effectively seal the capsule. The methodsthat are available to seal hard gelatin capsules are banding using agelatin band and sealing using a hydroalcoholic solution. The capsulesealing process uses the principle of lowering of the melting point ofgelatin by the application of moisture to the area between the capsulebody and cap. One machine for industrially sealing hard gelatin capsulesis commercially available and is marketed under the name LEMS™ 30(Liquid Encapsulation by Microspray). This machine is connected to theoutput of a capsule-filling machine by means of a conveyor.

Cannabinoid (e.g., dronabinol) hard gelatin room temperature stablecapsules can be manufactured using the Capsugel LEMS system andcapsule-filling machine (Bosch, Zanazzi etc.). Alternatively, they canalso be manufactured by using the banding method to seal the two halvesof the hard gelatin capsules (e.g. Shionogi HG capsule banding machine).Further (optional) methodology is known to those skilled in the art, andis set forth in various industry publications. (See, e.g., Cole, E. T.,Liquid Filled and Sealed Hard Gelatin Capsules, Capsugel Library(Originally published in Gattefosse Bulletin nr 92 (1992), incorporatedherein by reference.

Advantages of the Invention

The branded product Marinole (Dronabinol solution in soft gelatincapsules) is highly unstable at room temperature. Therefore themanufacturer of Marinol (Unimed Pharmaceuticals Inc.) recommends thatthe product be stored at refrigerated (2-8° C.) or cool (8-15° C.)conditions (Marinol package label, Physicians Desk Reference®, Ed.2003). Unlike the branded product Marinol, the present inventionprovides a cannabinoid (e.g., dronabinol) formulation drug product thatis preferably stable at all conditions—refrigerated, cool and roomtemperature (25° C./60% RH). Factors contributing to the improvedstability, particularly at room temperature, of the present inventioninclude: the absence of glycerin (glycerol) in the hard gelatin shellembodiment; low amounts of moisture in the hard gelatin shellembodiment; low permeability of oxygen through the shell of hard gelatincapsules; low sensitivity to heat and humidity of hard gelatin capsules;and the presence of sesamin and/or other antioxidants in theformulation. In certain embodiments, additional factors contributing toimproved stability of the cannabinoid dosage forms of the presentinvention include the addition of effective stabilizing amounts oforganic bases (e.g., ethanolamine and meglumine); and/or the addition ofadditional effective stabilizing amounts of anti-oxidants which may ormay not be inherently found in the oil-based carrier (for example,sesamin, lecithin and/or L-ascorbic acid-6-palmitate).

In certain preferred embodiments, the cannabinoid formulations of thepresent invention may improve the delivery of the cannabinoid withrespect to the extent, rate, and/or consistency of absorption from thegastrointestinal tract.

Uses of the Present Invention

The formulations of the present invention are useful in treatment andprevention of a very wide range of disorders, including, for example,nausea, vomiting, anorexia, cachexia, pain, gastrointestinal tractdistress (such as heartburn, indigestion, stomachache, sour stomach),inflammatory bowel disease, Crohn's disease, gastritis, irritable bowelsyndrome, ulcerative colitis, migraine headaches, postmenstrualsyndrome, Alzheimer's dementia, agitation, muscle spasms and otherinvoluntary movement disorders, Parkinson's disease andParkinsonian-type symptoms, spasticity as result of multiple sclerosis,glaucoma, anxiety disorders. Cannabinoids such as dronabinol have alsobeen reported as showing other biological activities which lendthemselves to possible therapeutic applications, such as in thetreatment of migraine headaches, spinal cord injury, anxiety, and as ananalgesic (e.g., to treat neuropathic pain). Cannabinoids such asdronabinol may be used together with opioid analgesics in a synergisticway to relieve pain; advantages of the combination may include decreasedadministration of opioids (leading to decreased side effects) and may beopioid-sparing (i.e., allowing for a reduced dose of opioid to achievean equivalent effect). Dronabinol has also been used in the treatment ofcancer cachexia (where the loss of appetite induces malnutrition incancer patients). It has also been used to treat movement disordersincluding dystonia, Huntington's disease, Parkinson's disease andTourette's syndrome; epilepsy, and for appetite stimulation inAlzheimer's disease. The use of cannabinoid formulations prepared inaccordance with the present invention is contemplated for any and all ofthe above uses, and any other use known or which become known to thoseskilled in the art.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The following examples illustrate various aspects of the presentinvention, and are set forth to assist in understanding the invention.These examples should not be construed as specifically limiting theinvention described and claimed herein. Variations of the invention,including the substitution of all equivalents now known or laterdeveloped, which would be within the purview of those skilled in theart, and changes in formulation or minor changes in experimental design,are considered to fall within the scope of the invention and appendedclaims.

The following equipment and procedure was used to develop and analyzeroom temperature stable dronabinol formulations:

-   Equipment-   Agilent 1100 HPLC-   Agilent 6890 GC-   Maxima™ Digital Mixer (Fischer Scientific)-   Isotemp Digital Hot-Plate Stirrer-   Glass Beakers-   Volumetric Flasks-   Ovens    Dissolution/Disintegration Procedure

An accurately measured volume (500 mL) of dissolution medium wastransferred to each of the 6 cylindrical glass vessels of the USPDissolution Apparatus 2. The apparatus was equilibrated at 37° C. for 1hour. One capsule was placed in each vessel and the capsules wereallowed to sink to the bottom of the vessel before starting the rotationof the blade. The rotation speed of the blade was maintained at 50 rpmduring the disintegration testing. The capsules were observed and thetime taken for each capsule shell to rupture was recorded. Rupture ofcapsule is identified by visual inspection of loss of integrity of thecapsule.

EXAMPLE 1 Manufacturing Procedure

Delta-9-tetrahydrocannabinol (dronabinol) is chemically synthesized asper procedures known to those skilled in the art, and is supplied as alight-yellow resinous oil that is sticky at room temperature and hardensupon refrigeration. Chemically synthesized dronabinol is supplied in around bottom flask with high-vacuum adaptor with a 24/40 o-ring sealjoint and bakeable PTFE plug.

Dronabinol in sesame oil is prepared as follows: An oil bath (vacuumpump oil, Fisher CAS #72623-87-1) was heated to 90-95° C. A flaskcontaining dronabinol warmed in the preheated oil bath (approx 10 min)until the dronabinol turned into a flowable liquid. The vacuum adapterof the flask was removed before warming the flask. Dronabinol wastransferred to a glass container by using a glass pipette and the exactamount transferred was noted. The actual amount of sesame oil to beadded to the mixture to obtain the required concentration of dronabinolwas calculated. Sesame oil (Sesame oil NF, RBDW (RBDW=refined, bleached,deodorized and winterized) stored at room temperature was transferred todronabinol container and the actual amount transferred was noted. Themixture containing dronabinol and sesame oil was again heated in the oilbath for approximately 5 minutes and thereafter mixed well by a vortexerfor 5 minutes. The resulting solution was cooled to room temperature anda sample was submitted for analysis.

EXAMPLE 2 Filling Hard Gelatin Capsules

A solvent solution for sealing hard gelatin capsules (1:1 ethanol to DIwater) was prepared by mixing equal amounts of alcohol and DI water. Thecap from the capsule was removed. 184 μL of formulation (equivalentvolume of 165 mg) prepared in accordance with Example 1 was filled inthe body of capsule by using DISTRIMAN®, a repetitive pipette. A smalllip brush was dipped into the sealing solution and applied to innerwalls of the cap. The body was immediately closed with the cap. Thefilled capsules were dried, transferred to clean glass bottles andstored at different temperature conditions (25° C./60% RH, 40° C./75% RHand 55° C.) for stability studies (see Stability Studies, below inExample 13). The capsules utilized in this procedure were size 3capsules containing 5 mg Dronabinol in a total of 165 mg solution(providing approximately a 3.03% drug concentration in the capsules).

EXAMPLE 3 Commercial Manufacture

An example of a potentially useful commercial manufacturing procedure isas follows:

-   1. Weigh required amount of Sesame Oil (e.g., approximately 50% of    total batch weight) of Sesame Oil in a clean stainless steel tank.-   2. Warm Sesame Oil to approximately 55±5° C. Maintain inert blanket    (any noble gas, e.g., nitrogen, helium, argon) during warming the    oil to prevent oxidation.-   3. Weigh the flask containing dronabinol and note the gross weight.    Heat the container under vacuum in a convection oven or oil bath or    water bath to approximately 95±5° C. until the raw material melts to    an easily flowable liquid. Ensure that the heating is uniform.    Record the heating time.-   4. Remove the adapter on the flask slowly and transfer dronabinol to    preheated Sesame Oil with Stirring. Rinse the raw material flask 2    to 3 times with portions of warm Sesame Oil. Add the rinses to    Sesame Oil container. Mix with an appropriate industrial mixer for    10 to 15 minutes. Record the mixing time.-   5. Weigh the raw material flask to obtain the tare weight. The    difference between the gross and tare weights will be the actual    amount transferred into the Sesame Oil.-   6. Wash the raw material container with a suitable organic solvent    (e.g. methanol, ethanol, dichloromethane). Collect the washings for    analysis.-   7. Reweigh the raw material container to obtain the weight of the    container after washing. Calculate the weight of dronabinol used in    formulating approx. 50% dronabinol solution.-   8. Conduct an HPLC assay of the 50% dronabinol solution. Determine    the exact dilution factor (e.g. 49.85% dronabinol)-   9. Calculate the additional amount of Sesame Oil to be added to the    mixture to obtain the required concentration of dronabinol (e.g.    12%, 6%, 3%, 1.5% w/w).-   10. Add slowly the calculated amount of warm Sesame Oil to the    mixture with stirring. Mix well for 15 to 20 minutes with steel    spatula or an appropriate blending apparatus.-   11. Cool the dronabinol solution to room temperature. Record the    cooling time.-   12. Submit a sample for analysis.

EXAMPLE 4 Commercial Filling in Hard Gelatin Capsules

An important aspect of a liquid-filling operation is the ability toeffectively seal the capsule. The methods that are available to sealhard gelatin capsules are, e.g., banding using a gelatin band andsealing using a hydroalcoholic solution. The capsule sealing processuses the principle of lowering of the melting point of gelatin by theapplication of moisture to the area between the capsule body and cap.The machine for industrially sealing hard gelatin capsules iscommercially available and is marketed under the name LEMS™ 30 (LiquidEncapsulation by Microspray). This machine is connected to the output ofa capsule-filling machine by means of a conveyor.

Dronabinol hard gelatin room temperature (“HG RT”) capsules may bemanufactured using the Capsugel LEMS system and capsule-filling machine(Bosch, Zanazzi etc.). Alternatively, they can also be manufactured byusing the banding method to seal the two halves of the hard gelatincapsules (e.g. Shionogi HG capsule banding machine).

EXAMPLE 5 Disintegration Studies

Disintegration studies were conducted on Dronabinol-sesame oilformulation filled hard gelatin capsules prepared in accordance with themethods described below. The formulation tested in Example 5 is a 5 mgcapsule of Delta-9-THC (3.03%) in sesame oil, super refined (Croda). Theformulation was a total of 165 mg and was encapsulated in size 3capsules.

The test that is most often associated with the assessment of in-vivoperformance is the dissolution test. In developing formulations,dissolution is used as a testing tool to select appropriate excipientsfor the formulation. The United States Pharmacopeia (USP) requires adissolution test for the branded product, Marinol, a liquid-filled softgelatin capsule, which is in reality a disintegration test. In thepresent study, USP Dissolution apparatus 2 was used for conducting allthe disintegration tests. The apparatus is described in section 711 ofthe USP.

Disintegration Medium: Water and buffer solutions listed below were usedas disintegration media with their pH adjusted to within ±0.05 units ofthe prescribed value.

-   1. Nanopure Water-   2. Phosphate Buffer (pH 1.2)-   3. Acetate Buffer (pH 4.5)-   4. Phosphate Buffer (pH 6.8)

Procedure: An accurately measured volume (500 ml) of dissolution mediumwas transferred to each of the 6 cylindrical glass vessels of the USPDissolution Apparatus 2. The apparatus was equilibrated at 37° C. for 1hour. One capsule was placed in each vessel and the capsules wereallowed to sink to the bottom of the vessel before starting the rotationof the blade. The rotation speed of the blade was maintained at 50 rpmduring the disintegration testing. The capsules were observed and thetime taken for each capsule shell to rupture was recorded. Rupture ofcapsule is identified by visual inspection of loss of integrity of thecapsule.

The disintegration times of six dronabinol USP 5 mg capsules used inExample 5 in Water and pH 1.2, 4.5 and 6.8 Buffer Solutions (as setforth above) are provided in Table 2. All the capsules disintegrated inless than 2 minutes (well within the USP monograph specification of 15minutes), irrespective of the disintegration medium used. These resultsindicate that the dronabinol capsules of Example 5 rapidly disintegratein all the media tested and therefore, dronabinol should be readilyavailable for absorption in any part of the gastro-intestinal tract.TABLE 2 Disintegration Times (Minutes) Sample No. Water PH 1.2 pH 4.5 pH6.8 1 1.40 1.37 0.62 0.70 2 1.15 0.57 0.22 0.90 3 1.43 0.57 0.22 0.70 40.60 0.85 1.32 0.48 5 0.82 0.63 0.62 0.45 6 1.12 0.57 1.45 0.57 Average1.09 0.76 0.74 0.63 Std. Dev. 0.33 0.32 0.53 0.17

The disintegration times for these capsules therefore meet the USPspecification of not more than 30 minutes for dronabinol capsules.

EXAMPLE 6 Stability Results—Presence of Moisture

In Example 6, a dronabinol formulation prepared in accordance withExample 1 and containing 5 mg dronabinol 3.03% w/w in sesame oil, superrefined (Croda) was prepared. Water was added to the formulation, andthe formulation was vortexed for several hours. Thereafter, theformulation was separated from remaining water after centrifugation.Although no measurements/calculations were performed to calculate theamount of water in the formulation, it is believed that the formulationwould be saturated with water since it was mixed for several hours. Theformulation was stored in amber glass vials at 55° C. for 2 weeks whilebeing tested for stability. The rationale for performing stabilitystudies at 55° C. for 2 weeks was based on the hypothesis that the dataobtained would be a good representation of two-year shelf life of theproduct stored at room temperature.

The results of stability testing of Example 6 are set forth in Table 3below. TABLE 3 RELATED FORMU- TOTAL SUBSTANCES CONDI- LATION ASSAY IMPU-D8THC CBN CBD TION # % RITY % % % % Zero Time Example 9-ii* 93.80 6.200.75 1.88 0.29 55° C. Example 9-ii* 82.16 17.84 0.72 1.86 0.23 (1 week)Example 6 77.67 22.33 0.49 1.92 0.09 55° C. Example 9-ii 67.41 32.591.06 4.96 4.20 (2 weeks) Example 6 62.71 37.29 0.60 2.70 0.23*Control

The moisture saturation studies conducted on dronabinol solution insesame oil indicate significant instability of the active ingredientdronabinol. In particular, the assay showed that the level of activedrug fell below 90% of its initial amount within one week of storage at55° C., with significant amounts of impurities present. The levels ofthe degradants D8THC, CBN and CBD continued to rise significantly duringthe storage period. Based on the stability results, it was determinedthat the formulation of Example 6 lacked sufficient stability, e.g., toobtain a two-year shelf-life. The cause of this lack of stability ishypothesized as being due to the presence of moisture and the lack ofsufficient anti-oxidant(s) in the formulation to prevent degradation ofthe dronabinol in that environment (super-refined sesame oil was foundto lack such ingredients; see below).

Extended Stability Results—Presence of Moisture

To confirm whether the presence of moisture and lack of sufficientantioxidants caused a lack of stability and an increase in dronabinolrelated impurities such as delta-8-THC, CBD and CBN, stability studiesat room temperature and at accelerated conditions over an extendedperiod of time were conducted using sesame oil from Arista, Croda andDipasa.

EXAMPLE 6A Dronabinol Solution in Sesame Oil Sourced fromArista—Capsules

In Example 6A, dronabinol formulations were prepared in accordance withExample 6, using sesame oil sourced from Arista. The formulation inExample 6A was exposed to moisture in accordance with the process inExample 6. The dronabinol formulation was then used to fill hard gelatincapsules in accordance with Example 2. The formulation within thecapsules was initially tested, then tested at 25° C. for 3 and 6 months;40° C. for 1, 2 and 3 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 6A at 25° C. are set forthin Table 4 below. TABLE 4 Total Impurities Moisture Potency CBD CBND8-THC Increase + 25° C. % % % % % % Zero 100% 100.00 0.02 0.54 0.513.82  50% 100.00 0.01 0.60 0.58 4.31 3 Months 100% 89.24 0.16 0.85 0.5011.31 7.49  50% 90.36 0.15 0.88 0.49 11.48 7.17 6 Months 100% 90.19 1.110.99 0.49 13.56 9.74  50% 91.38 1.08 1.06 0.49 13.25 8.94

The results of stability testing of Example 6A 40° C. are set forth inTable 5 below. TABLE 5 Total Impurities Moisture Potency CBD CBN D8-THCIncrease + 40° C. % % % % % % Zero 100% 100.00 0.02 0.54 0.51 3.82  50%100.00 0.01 0.60 0.58 4.31 1 Month 100% 90.76 0.47 0.96 0.55 10.96 7.14 50% 91.93 0.56 0.79 0.55 9.96 5.65 2 Months 100% 88.36 0.37 1.10 0.6512.46 8.64  50% 90.08 0.33 0.95 0.53 11.15 6.84 3 Months 100% 85.90 0.361.64 0.43 13.23 9.41  50% 88.95 0.60 1.46 0.49 12.84 8.53

The results of stability testing of Example 6A 55° C. are set forth inTable 6 below. TABLE 6 Total Impurities Moisture Potency CBD CBN D8-THCIncrease + 55° C. % % % % % % Zero 100% 100.00 0.02 0.54 0.51 3.82  50%100.00 0.01 0.60 0.58 4.31 1 Week 100% 91.00 0.06 0.58 0.50 11.15 7.33 50% 88.82 0.04 0.69 0.44 14.74 10.43 2 Weeks 100% 75.08 0.01 1.05 0.4622.54 18.72  50% 71.65 0.01 1.47 0.50 25.45 21.14

In Example 6B, dronabinol formulations were prepared in accordance withExample 6A, using sesame oil sourced from Croda. The formulation inExample 6B was exposed to moisture in accordance with the process inExample 6. The dronabinol formulation was then used to fill hard gelatincapsules in accordance with Example 2. The formulation within thecapsules was initially tested, then tested at 25° C. for 3 and 6 months;40° C. for 1, 2 and 3 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 6B at 25° C. are set forthin Table 7 below:

tested, then tested at 25° C. for 3 and 6 months; 40° C. for 1, 2 and 3months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 6B at 25° C. are set forthin Table 7 below: TABLE 7 Total Impurities Moisture Potency CBD CBND8-THC Increase + 25° C. % % % % % % Zero 100% 100.00 0.02 0.43 0.575.05  50% 100.00 0.01 0.48 0.58 4.32 3 Months 100% 88.26 0.18 0.65 0.5412.74 7.69  50% 86.98 0.20 0.60 0.54 12.60 8.28 6 Months 100% 90.33 1.380.80 0.51 15.08 10.03  50% 88.85 1.70 0.86 0.58 16.05 11.73

The results of stability testing of Example 6B at 40° C. are set forthin Table 8 below: TABLE 8 Total Impurities Moisture Potency CBD CBN D8-Increase + 40° C. % % % THC % % % Zero 100% 100.00 0.02 0.43 0.57 5.0550% 100.00 0.01 0.48 0.58 4.32 1 Month 100% 91.91 1.06 0.72 0.57 12.777.72 50% 89.41 0.94 0.82 0.62 12.60 8.28 2 Months 100% 88.85 0.65 0.980.71 14.18 9.13 50% 86.80 0.62 0.95 0.62 13.85 9.53 3 Months 100% 84.630.99 1.68 0.58 16.13 11.08 50% 82.81 0.95 1.54 0.56 15.92 11.60

The results of stability testing of Example 6B at 55° C. are set forthin Table 9 below: TABLE 9 Total Impurities Moisture Potency CBD CBN D8-Increase + 55° C. % % % THC % % % Zero 100% 100.00 0.02 0.43 0.57 5.0550% 100.00 0.01 0.48 0.58 4.32 1 Week 100% 87.71 0.08 0.58 0.57 15.2010.15 50% 87.30 0.05 0.54 0.56 16.86 12.54 2 Weeks 100% 21.81 0.11 2.990.53 70.45 65.40 50% 69.85 0.22 1.31 0.57 31.44 27.12

In Example 6C, dronabinol formulations were prepared in accordance withExample 6, using sesame oil sourced from Dipasa. The formulation inExample 6C was exposed to moisture in accordance with the process inExample 6. The dronabinol formulation was then used to fill hard gelatincapsules in accordance with Example 2. The formulation within thecapsules was initially tested, then tested at 25° C. for 3 and 6 months;40° C. for 1, 2 and 3 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 6C of 25° C. are set forthin Table 10 below: TABLE 10 Total Impurities Moisture Potency CBD CBND8- Increase + 25° C. % % % THC % % % Zero 100% 100.00 0.02 0.54 0.604.11 50% 100.00 0.01 0.52 0.55 3.89 3 Months 100% 92.95 0.06 0.64 0.516.08 1.97 50% 96.01 0.07 0.67 0.56 5.98 2.09 6 Months 100% 94.18 0.420.88 0.52 8.67 4.56 50% 96.03 0.40 0.85 0.56 8.59 4.70

The results of stability of Example 6C at 40° C. are set forth in Table11 below: TABLE 11 Total Impurities Moisture Potency CBD CBN D8-Increase + 40° C. % % % THC % % % Zero 100% 100.00 0.02 0.54 0.60 4.1150% 100.00 0.01 0.52 0.55 3.89 1 Month 100% 94.43 0.19 0.68 0.59 7.303.19 50% 94.40 0.22 0.80 0.61 8.50 4.61 2 Months 100% 88.61 0.19 0.940.58 10.81 6.70 50% 90.03 0.20 1.11 0.57 11.68 7.79 3 Months 100% 86.340.22 1.62 0.53 12.78 8.67 50% 88.03 0.22 1.79 0.54 13.80 9.91

The results of stability of Example 6C at 50° C. as set forth in Table12 below: TABLE 12 Total Impurities Moisture Potency CBD CBN D8-Increase + 55° C. % % % THC % % % Zero 100% 100.00 0.02 0.54 0.60 4.1150% 100.00 0.01 0.52 0.55 3.89 1 Week 100% 95.76 0.03 0.62 0.54 6.622.51 50% 98.81 0.02 0.73 0.55 7.00 3.11 2 Weeks 100% 93.01 0.01 0.770.60 9.38 5.27 50% 93.75 0.01 1.12 0.56 9.52 5.63

EXAMPLE 6D

In Example 6D, dronabinol formulations were prepared in accordance withExample 6, using sesame oil sourced from Arista. The formulation inExample 6D was exposed to moisture in accordance with the process inExample 6. The formulation was then used to fill amber glass vials. Theformulation within the vials was initially tested, then tested at 25° C.for 3 and 6 months; 40° C. for 1, 2 and 3 months and at 55° C. for 1 and2 weeks.

The results of stability of Example 6D at 25° C. as set forth in Table13 below: TABLE 13 Total Impurities Moisture Potency CBD D8- Increase +25° C. % % CBN % THC % % % Zero 100% 100.00 0.02 0.54 0.51 3.82 50%100.00 0.01 0.60 0.58 4.31 3 Months 100% 94.96 0.24 0.52 0.47 5.51 1.6950% 95.67 0.15 0.54 0.48 5.34 1.03 6 Months 100% 97.86 0.31 0.60 0.547.85 4.03 50% 97.85 0.25 0.61 0.54 7.90 3.59

The results of stability of Example 6D at 40° C. as set forth in Table14 below: TABLE 14 Total Impurities Moisture Potency CBD D8- Increase +40° C. % % CBN % THC % % % Zero 100% 100.00 0.02 0.54 0.51 3.82 50%100.00 0.01 0.60 0.58 4.31 1 Month 100% 90.14 0.63 0.60 0.55 11.93 8.1150% 95.28 0.07 0.47 0.55 6.32 2.01 2 Months 100% 80.52 1.01 1.03 0.5618.47 14.65 50% 91.10 0.34 0.59 0.57 10.33 6.02 3 Months 100% 73.36 1.151.83 0.52 24.85 21.03 50% 86.45 1.33 1.08 0.53 17.82 13.51

The results of stability of Example 6D at 55° C. as set forth in Table15 below: TABLE 15 Total Impurities Moisture Potency CBD D8- Increase +55° C. % % CBN % THC % % % Zero 100% 100.00 0.02 0.54 0.51 3.82 50%100.00 0.01 0.60 0.58 4.31 1 Week 100% 91.00 0.06 0.58 0.50 11.15 7.3350% 88.82 0.04 0.69 0.44 14.74 10.43 2 Weeks 100% 75.08 0.01 1.05 0.4622.54 18.72 50% 71.65 0.01 1.47 0.50 25.45 21.14

EXAMPLE 6E

In Example 6E, dronabinol formulations were prepared in accordance withExample 6, using sesame oil sourced from Croda. The formulation inExample 6E was exposed to moisture in accordance with the process inExample 6. The formulation was then used to fill amber glass vials. Theformulation within the vials was initially tested, then tested at 25° C.for 3 and 6 months; 40° C. for 1, 2 and 3 months and at 55° C. for 1 and2 weeks.

The results of stability of Example 6E at 25° C. as set forth in Table16 below: TABLE 16 Total Impurities Moisture Potency CBD D8- Increase +25° C. % % CBN % THC % % % Zero 100% 100.00 0.02 0.43 0.57 5.05 50%100.00 0.01 0.48 0.58 4.32 3 Months 100% 59.35 5.07 1.25 0.52 39.3734.32 50% 75.87 3.25 0.84 0.52 25.17 20.85 6 Months 100% 47.17 5.48 2.130.64 50.49 45.44 50% 67.70 3.75 1.23 0.62 32.62 28.30

The results of stability of Example 6E at 40° C. as set forth in Table17 below: TABLE 17 Total Impurities Moisture Potency CBD D8- Increase +40° C. % % CBN % THC % % % Zero 100% 100.00 0.02 0.43 0.57 5.05 50%100.00 0.01 0.48 0.58 4.32 1 Month 100% 31.99 6.67 3.01 0.59 62.69 57.6450% 84.75 2.40 0.62 0.58 17.83 13.51 2 Months 100% 22.90 5.35 3.72 0.6266.06 61.01 50% 74.41 3.52 1.12 0.56 24.48 20.16 3 Months 100% 16.934.18 6.54 1.06 72.54 67.49 50% 64.95 3.62 1.41 0.54 30.28 25.96

The results of stability of Example 6E at 55° C. as set forth in Table18 below: TABLE 18 Total Impurities Moisture Potency CBD D8- Increase +55° C. % % CBN % THC % % % Zero 100% 100.00 0.02 0.43 0.57 5.05 50%100.00 0.01 0.48 0.58 4.32 1 Week 100% 87.71 0.08 0.58 0.57 15.20 10.1550% 87.30 0.05 0.54 0.56 16.86 12.54 2 Weeks 100% 21.81 0.11 2.99 0.5370.45 65.40 50% 69.85 0.22 1.31 0.57 31.44 27.12

EXAMPLE 6F

In Example 6F, dronabinol formulations were prepared in accordance withExample 6, using sesame oil sourced from Dipasa. The formulation inExample 6F was exposed to moisture in accordance with the process inExample 6. The formulation was then used to fill amber glass vials. Theformulation within the vials was initially tested, then tested at 25° C.for 3 and 6 months; 40° C. for 1, 2 and 3 months and at 55° C. for 1 and2 weeks.

The results of stability of Example 6F at 25° C. as set forth in Table19 below: TABLE 19 Total Impurities Moisture Potency CBD D8- Increase +25° C. % % CBN % THC % % % Zero 100% 100.00 0.02 0.54 0.60 4.11 50%100.00 0.01 0.52 0.55 3.89 3 Months 100% 91.32 0.23 0.60 0.53 6.30 2.1950% 95.43 0.28 0.71 0.53 6.06 2.17 6 Months 100% 93.79 0.29 0.76 0.5510.24 6.13 50% 96.77 0.32 0.96 0.56 8.80 4.91

The results of stability of Example 6F at 40° C. as set forth in Table20 below: TABLE 20 Total Impurities Moisture Potency CBD D8- Increase +40° C. % % CBN % THC % % % Zero 100% 100.00 0.02 0.54 0.60 4.11 50%100.00 0.01 0.52 0.55 3.89 1 Month 100% 92.81 0.14 0.54 0.59 7.78 3.6750% 94.40 0.12 0.70 0.60 7.24 3.35 2 Months 100% 86.15 0.43 0.79 0.6013.86 9.75 50% 91.50 0.33 1.11 0.62 10.35 6.46 3 Months 100% 81.13 0.691.58 0.54 20.90 16.79 50% 91.88 0.36 1.88 0.58 14.48 10.59

The results of stability of Example 6F at 55° C. as set forth in Table21 below: TABLE 21 Total Impurities Moisture Potency D8- Increase + 55°C. % CBD % CBN % THC % % % Zero 100% 100.00 0.02 0.54 0.60 4.11 50%100.00 0.01 0.52 0.55 3.89 1 Week 100% 95.76 0.03 0.62 0.54 6.62 2.5150% 98.81 0.02 0.73 0.55 7.00 3.11

As can be seen, the dronabinol formulations are generally unstable inthe presence of moisture. However, the dronabinol formulation utilizingsesame oil sourced from Dipasa is resistant to some extent fromdegradation due to the presence of moisture. This stability can beattributed to the presence of high levels of the antioxidant lecithin insesame oil sourced from Dipasa.

EXAMPLE 7 Stability Results—Addition of Glycerin/Glycerol

In Example 7, the effect of added glycerin in dronabinol formulated in asesame oil solution was evaluated. In each of Examples 7i-7v, thespecified amount of glycerin was added to the formulation prepared inaccordance with Example 1. The formulations were stored in HPLC amberglass vials.

Example 7-i contains 5 mg dronabinol solution (3.03% w/w) and 1% (w/v)glycerin in sesame oil, super refined NF (by Croda).

Example 7-ii contains 5 mg dronabinol solution (3.03% w/w) and 0.2%(w/v) glycerin in sesame oil, super refined NF (by Croda).

Example 7-iii contains 5 mg dronabinol solution (3.03% w/w) and 0.1%(w/v) glycerin in sesame oil, super refined NF (by Croda).

Example 7-iv contains 5 mg dronabinol solution (3.03% w/w) and 0.02%(w/v) glycerin in sesame oil, super refined NF (by Croda).

Example 7-v contains 5 mg dronabinol solution (3.03% w/w) and 0.002%(w/v) glycerin in sesame oil, super refined NF (by Croda).

As set forth above, the formulations tested in Example 7 each include 5mg dronabinol (3.03%) in sesame oil, the formulation having a total of165 mg per sample was transferred to amber glass vials for storage.Comparison Example 9-ii is a formulation prepared in the same manner asExamples 7-i-7v, except there was no added glycerin in Example 9-ii.

A summary of the compositions of Examples 7-i-7v is set forth in Table22 below: TABLE 22 Composition Formulation Dronabinol Sesame Oil OtherIngredients Example 7-i 3.03% w/w QS Glycerin (1%) Example 7-ii 3.03%w/w QS Glycerin (0.2%) Example 7-iii 3.03% w/w QS Glycerin (0.1%)Example 7-iv 3.03% w/w QS Glycerin (0.02%) Example 7-v 3.03% w/w QSGlycerin (0.002%)

The formulations of Example 7 were then subjected to stability studiesunder conditions of 55° C. for one week and 55° C. for two weeks,respectively.

The results are provided in Table 23 below: TABLE 23 TOTAL RELATEDSUBSTANCES CONDITION FORMULATION # ASSAY % IMPURITY % D8THC % CBN % CBD% Zero Time Example 9-ii* 93.80 6.20 0.75 1.88 0.29 (no added Glycerin)55° C. Example 9-ii* 82.16 17.84 0.72 1.86 0.23 (1 week) (no glycerinadded) Example 7-i 80.84 19.16 0.56 1.87 0.13 (1% Glycerin) Example 7-ii77.64 22.36 0.72 1.77 0.14 (0.2% Glycerin) Example 7-iii 77.57 22.430.56 1.73 0.12 (0.1% Glycerin) Example 7-iv 80.57 19.43 0.47 1.60 0.16(0.02% Glycerin) Example 7-v 79.55 20.45 0.58 1.40 0.19 (0.002%Glycerin) 55° C. Example 9-ii 67.41 32.59 1.06 4.96 0.29 (2 weeks) (noglycerin added) Example 7-i 61.35 38.65 0.16 2.98 0.76 (1% Glycerin)Example 7-ii 63.54 36.46 0.16 2.87 0.72 (0.2% Glycerin) Example 7-iii62.71 37.29 0.19 2.96 0.79 (0.1% Glycerin) Example 7-iv 64.04 35.96 0.182.84 0.88 (0.02% Glycerin) Example 7-v 66.02 33.98 0.17 2.79 0.77(0.002% Glycerin)*Control

Based on the results set forth in Table 23, it is clear that dronabinolis highly unstable in the presence of glycerin. In fact, over a third ofthe active ingredient dronabinol is lost to degradation in two weeks at55° C. when exposed to even small quantities of glycerin (0.002%).

Extended Stability Results—Addition of Glycerin/Glycerol

To confirm whether the addition of varying amounts of glycerin indronabinol formulations caused a lack of stability and increase indronabinol related impurities such as delta-8-THC, CBD, and CBN,stability studies at room temperature and at accelerated conditions overan extended period of time were conducted using sesame oil from Arista,Croda and Dipasa.

EXAMPLE 7A Dronabinol Solution in Sesame Oil Sourced from Arista, withVarying Amounts of Glycerin Added

In Example 7A, the effect of added varying amounts of glycerin indronabinol formulations using sesame oil sourced from Arista wasevaluated. In each of Examples 7A-i-7A-v, the specified amount ofglycerin added was prepared in accordance with Example 7. Theformulations were then used to fill hard gelatin capsules in accordancewith Example 2. The formulations within the capsules were initiallytested, then tested at 25° C. for 3 and 6 months; 40° C. for 1, 2 and 3months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Examples 7A-i-7A-v at 25° C. are setforth in Table 24 below. TABLE 24 Glycerin Total Impurities 25° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero (7A-i) 1% 100.00 0.020.65 0.56 3.90 (7A-ii) 0.2% 100.00 0.01 0.51 0.52 3.70 (7A-iii) 0.1%100.00 0.02 0.63 0.58 3.81 (7A-iv) 100.00 0.01 0.59 0.49 3.96 0.02%(7A-v) 100.00 0.02 0.54 0.52 3.95 0.002% 3 (7A-i) 1% 89.05 0.12 0.700.44 10.91 7.01 Months (7A-ii) 0.2% 88.70 0.18 0.77 0.45 11.20 7.50(7A-iii) 0.1% 92.12 0.11 0.76 0.50 11.07 7.26 (7A-iv) 90.44 0.21 0.810.49 11.26 7.30 0.02% (7A-v) 91.13 0.17 0.82 0.48 11.08 7.13 0.002% 6(7A-i) 1% 91.25 1.14 0.82 0.48 12.17 8.27 Months (7A-ii) 0.2% 90.91 1.100.95 0.47 12.71 9.01 (7A-iii) 0.1% 92.97 1.07 1.00 0.48 12.68 8.87(7A-iv) 91.41 0.21 0.81 0.49 11.26 7.30 0.02% (7A-v) 92.36 1.07 1.120.51 13.34 9.39 0.002%

The results of stability testing of Examples 7A-i-7A-v at 40° C. are setforth in Table 25 below. TABLE 25 Glycerin Total Impurities 40° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero (7A-i) 1% 100.00 0.020.65 0.56 3.90 (7A-ii) 0.2% 100.00 0.01 0.51 0.52 3.70 (7A-iii) 0.1%100.00 0.02 0.63 0.58 3.81 (7A-iv) 100.00 0.01 0.59 0.49 3.96 0.02%(7A-v) 100.00 0.02 0.54 0.52 3.95 0.002% 1 (7A-i) 1% 90.27 0.64 0.770.53 9.93 6.03 Month (7A-ii) 0.2% 106.03 0.57 0.79 0.53 9.88 6.18(7A-iii) 0.1% 92.63 0.53 0.83 0.52 9.88 6.07 (7A-iv) 91.00 0.51 0.830.52 9.74 5.78 0.02% (7A-v) 91.94 0.49 0.93 0.51 10.26 6.31 0.002% 2(7A-i) 1% 88.22 0.35 1.04 0.46 10.89 6.99 Months (7A-ii) 0.2% 88.08 0.321.07 0.80 11.77 8.07 (7A-iii) 0.1% 92.00 0.29 1.23 0.96 12.56 8.75(7A-iv) 89.81 0.26 1.13 0.54 11.81 7.85 0.02% (7A-v) 89.34 0.28 1.170.53 11.75 7.80 0.002% 3 (7A-i) 1% 86.71 0.42 1.49 0.45 12.45 8.55Months (7A-ii) 0.2% 86.78 0.37 1.63 0.47 13.03 9.33 (7A-iii) 0.1% 88.380.38 1.63 0.47 13.07 9.26 (7A-iv) 88.10 0.35 1.61 0.51 12.85 8.89 0.02%(7A-v) 87.64 0.34 1.81 0.46 13.87 9.92 0.002%

The results of stability testing of Examples 7A-i-7A-v at 55° C. are setforth in Table 26 below. TABLE 26 Glycerin Total Impurities 55° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero (7A-i) 1% 100.00 0.020.65 0.56 3.90 (7A-ii) 0.2% 100.00 0.01 0.51 0.52 3.70 (7A-iii) 0.1%100.00 0.02 0.63 0.58 3.81 (7A-iv) 0.02% 100.00 0.01 0.59 0.49 3.96(7A-v) 0.002% 100.00 0.02 0.54 0.52 3.95 1 (7A-i) 1% 86.50 0.01 0.790.48 15.02 11.12 Week (7A-ii) 0.2% 92.73 0.01 0.72 0.51 13.58 9.88(7A-iii) 0.1% 90.61 0.01 0.79 0.52 12.90 9.09 (7A-iv) 0.02% 88.88 0.020.71 0.49 15.10 11.14 (7A-v) 0.002% 88.77 0.02 0.80 0.49 16.67 12.72 2(7A-i) 1% 42.43 0.06 3.04 0.48 48.24 44.34 Weeks (7A-ii) 0.2% 46.43 0.042.66 0.45 44.57 40.87 (7A-iii) 0.1% 42.78 0.04 3.14 0.58 48.10 44.29(7A-iv) 0.02% 38.99 0.03 3.01 0.48 51.96 48.00 (7A-v) 0.002% 37.79 0.043.08 0.44 52.66 48.71

EXAMPLE 7B Dronabinol Solution in Sesame Oil Sourced from Croda, withVarying Amounts of Glycerin Added

In Example 7B, the effect of added varying amounts glycerin indronabinol formulation using sesame oil sourced from Croda wasevaluated. In each of Examples 7B-i-7B-v, the specified amount ofglycerin added was prepared in accordance with Example 7. Theformulations were then used to fill hard gelatin capsules in accordancewith Example 2. The formulations within the capsules were initiallytested, then tested at 25° C. for 3 and 6 months; 40° C. for 1, 2 and 3months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Examples 7B-i-7B-v at 25° C. are setforth in Table 27 below. TABLE 27 Glycerin Total Impurities 25° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero (7B-i) 1% 100.00 0.030.50 0.59 3.79 (7B-ii) 0.2% 100.00 0.01 0.49 0.61 4.09 (7B-iii) 0.1%100.00 0.01 0.47 0.60 4.00 (7B-iv) 100.00 0.02 0.50 0.60 3.90 0.02%(7B-v) 100.00 0.02 0.49 0.60 4.12 0.002% 3 (7B-i) 1% 85.70 0.15 0.530.55 12.54 8.75 Months (7B-ii) 0.2% 87.57 0.19 0.60 0.55 12.55 8.46(7B-iii) 0.1% 87.43 0.21 0.61 0.55 12.73 8.73 (7B-iv) 87.37 0.29 0.580.55 12.27 8.37 0.02% (7B-v) 88.13 0.30 0.59 0.56 12.84 8.72 0.002% 6(7B-i) 1% 88.20 1.35 0.64 0.55 13.77 9.98 Months (7B-ii) 0.2% 88.72 1.560.72 0.60 15.15 11.06 (7B-iii) 0.1% 88.16 1.34 0.75 0.55 14.45 10.45(7B-iv) 88.21 1.37 0.74 0.53 13.81 9.91 0.02% (7B-v) 88.65 1.30 0.790.53 14.79 10.67 0.002%

The results of stability testing of Examples 7B-i-7B-v at 40° C. are setforth in Table 28 below. TABLE 28 Glycerin Total Impurities 40° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero (7B-i) 1% 100.00 0.030.50 0.59 3.79 (7B-ii) 0.2% 100.00 0.01 0.49 0.61 4.09 (7B-iii) 0.1%100.00 0.01 0.47 0.60 4.00 (7B-iv) 100.00 0.02 0.50 0.60 3.90 0.02%(7B-v) 100.00 0.02 0.49 0.60 4.12 0.002% 1 (7B-i) 1% 88.51 1.15 0.600.61 12.28 8.49 Month (7B-ii) 0.2% 89.51 1.02 0.71 0.59 12.26 8.17(7B-iii) 0.1% 90.14 0.98 0.66 0.58 11.88 7.88 (7B-iv) 88.81 0.97 0.720.57 12.07 8.17 0.02% (7B-v) 90.06 1.08 0.71 0.58 12.18 8.06 0.002% 2(7B-i) 1% 85.59 0.82 0.73 0.60 13.32 9.53 Months (7B-ii) 0.2% 85.39 0.670.90 0.81 13.25 9.16 (7B-iii) 0.1% 86.54 0.67 0.86 0.59 13.29 9.29(7B-iv) 86.16 0.65 0.88 0.62 13.49 9.59 0.02% (7B-v) 87.71 0.59 0.960.60 13.75 9.63 0.002% 3 (7B-i) 1% 83.33 1.12 1.23 0.57 14.70 10.91Months (7B-ii) 0.2% 84.36 1.00 1.48 0.59 15.38 11.29 (7B-iii) 0.1% 83.950.89 1.47 0.56 14.86 10.86 (7B-iv) 84.81 1.00 1.39 0.60 14.73 10.830.02% (7B-v) 84.53 0.86 1.77 0.57 15.30 11.18 0.002%

The results of stability testing of Examples 7B-i-7B-v at 55° C. are setforth in Table 29 below. TABLE 29 Glycerin Total Impurities 55° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero (7B-i) 1% 100.00 0.030.50 0.59 3.79 (7B-ii) 0.2% 100.00 0.01 0.49 0.61 4.09 (7B-iii) 0.1%100.00 0.01 0.47 0.60 4.00 (7B-iv) 100.00 0.02 0.50 0.60 3.90 0.02%(7B-v) 100.00 0.02 0.49 0.60 4.12 0.002% 1 (7B-i) 1% 84.97 0.01 0.750.56 15.42 11.63 Week (7B-ii) 0.2% 86.55 0.05 0.71 0.57 18.20 14.11(7B-iii) 0.1% 84.25 0.10 0.76 0.52 20.65 16.63 (7B-iv) 86.91 0.08 0.660.55 17.86 13.96 0.02% (7B-v) 84.44 0.11 0.76 0.53 20.93 16.81 0.002% 2(7B-i) 1% 67.98 0.01 1.78 0.55 24.93 21.14 Weeks (7B-ii) 0.2% 26.76 0.182.76 0.71 65.03 60.94 (7B-iii) 0.1% 65.98 0.19 1.42 0.54 33.00 29.00(7B-iv) 21.93 0.34 3.26 0.64 71.79 67.89 0.02% (7B-v) 19.08 0.14 3.660.67 72.97 68.85 0.002%

EXAMPLE 7C Dronabinol Solution in Sesame Oil Sourced from Dipasa, withVarying Amounts of Glycerin Added

In Example 7C, the effect of added varying amounts glycerin indronabinol formulation using sesame oil sourced from Dipasa wasevaluated. In each of Examples 7C-i-7C-v, the specified amount ofglycerin added was prepared in accordance with Example 7. Theformulations were then used to fill hard gelatin capsules in accordancewith Example 2. The formulations within the capsules were initiallytested, then tested at 25° C. for 3 and 6 months; 40° C. for 1, 2 and 3months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Examples 7C-i-7C-v at 25° C. are setforth in Table 30 below. TABLE 30 Glycerin Total Impurities 25° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero (7C-i) 1% 100.00 0.030.56 0.63 3.99 (7C-ii) 0.2% 100.00 0.01 0.66 0.57 3.99 (7C-iii) 0.1%100.00 0.01 0.55 0.60 4.04 (7C-iv) 100.00 0.03 0.54 0.57 4.05 0.02%(7C-v) 100.00 0.01 0.54 0.56 3.89 0.002% 3 (7C-i) 1% 94.52 0.02 0.700.55 5.87 1.88 Months (7C-ii) 0.2% 96.88 0.04 0.64 0.50 6.22 2.23(7C-iii) 0.1% 96.09 0.04 0.61 0.54 5.93 1.89 (7C-iv) 95.47 0.06 0.620.53 6.23 2.18 0.02% (7C-v) 95.37 0.05 0.61 0.54 5.93 2.04 0.002% 6(7C-i) 1% 96.79 0.39 0.83 0.54 8.54 4.55 Months (7C-ii) 0.2% 97.04 0.480.80 0.56 8.91 4.92 (7C-iii) 0.1% 97.85 0.40 0.79 0.53 8.52 4.48 (7C-iv)96.52 0.41 0.90 0.55 8.80 4.75 0.02% (7C-v) 96.69 0.37 0.75 0.59 8.474.58 0.002%

The results of stability testing of Examples 7C-i-7C-v at 40° C. are setforth in Table 31 below. TABLE 31 Glycerin Total Impurities 40° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero (7C-i) 1% 100.00 0.030.56 0.63 3.99 (7C-ii) 0.2% 100.00 0.01 0.66 0.57 3.99 (7C-iii) 0.1%100.00 0.01 0.55 0.60 4.04 (7C-iv) 100.00 0.03 0.54 0.57 4.05 0.02%(7C-v) 100.00 0.01 0.54 0.56 3.89 0.002% 1 (7C-i) 1% 94.94 0.24 0.670.59 7.38 3.39 Month (7C-ii) 0.2% 94.94 0.20 0.71 0.57 7.81 3.82(7C-iii) 0.1% 96.35 0.19 0.68 0.57 6.98 2.94 (7C-iv) 95.18 0.23 0.790.57 8.30 4.25 0.02% (7C-v) 93.71 0.23 0.82 0.57 8.65 4.76 0.002% 2(7C-i) 1% 90.09 0.25 0.99 0.60 11.08 7.09 Months (7C-ii) 0.2% 91.06 0.211.03 0.62 11.06 7.07 (7C-iii) 0.1% 95.29 0.23 0.94 0.58 10.84 6.80(7C-iv) 90.14 0.18 1.14 0.57 11.67 7.62 0.02% (7C-v) 90.40 0.15 1.110.59 11.22 7.33 0.002% 3 (7C-i) 1% 87.89 0.26 1.53 0.53 12.48 8.49Months (7C-ii) 0.2% 90.10 0.26 1.61 0.53 12.64 8.65 (7C-iii) 0.1% 89.440.38 1.61 0.56 12.87 8.83 (7C-iv) 88.31 0.35 1.67 0.54 13.07 9.02 0.02%(7C-v) 88.82 0.22 1.57 0.56 12.50 8.61 0.002%

The results of stability testing of Examples 7C-i-7C-v at 55° C. are setforth in Table 32 below. TABLE 32 Glycerin Total Impurities 55° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero (7C-i) 1% 100.00 0.030.56 0.63 3.99 (7C-ii) 0.2% 100.00 0.01 0.66 0.57 3.99 (7C-iii) 0.1%100.00 0.01 0.55 0.60 4.04 (7C-iv) 100.00 0.03 0.54 0.57 4.05 0.02%(7C-v) 100.00 0.01 0.54 0.56 3.89 0.002% 1 (7C-i) 1% 96.81 0.02 0.720.53 6.99 3.00 Week (7C-ii) 0.2% 98.85 0.04 0.75 0.55 7.23 3.24 (7C-iii)0.1% 98.53 0.03 0.80 0.55 7.32 3.28 (7C-iv) 97.55 0.04 0.82 0.58 7.833.78 0.02% (7C-v) 96.92 0.04 0.54 0.56 7.88 3.99 0.002% 2 (7C-i) 1%93.18 0.01 0.99 0.60 9.38 5.39 Weeks (7C-ii) 0.2% 92.04 0.01 1.09 0.539.64 5.65 (7C-iii) 0.1% 92.80 0.01 1.12 0.57 10.48 6.44 (7C-iv) 91.550.01 1.20 0.57 10.75 6.70 0.02% (7C-v) 89.74 0.01 1.31 0.52 11.18 7.290.002%

EXAMPLE 7D Dronabinol Solution in Sesame Oil Sourced from Arista, withVarying Amounts of Glycerin Added

In Example 7D, the effect of added varying amounts glycerin indronabinol formulation using sesame oil sourced from Arista wasevaluated. In each of Examples 7D-i-7D-v, the specified amount ofglycerin added was prepared in accordance with Example 7. Theformulations were then used to fill amber glass vials. The formulationswithin the vials were initially tested, then tested at 25° C. for 3 and6 months; 40° C. for 1, 2 and 3 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Examples 7D-i-7D-v at 25° C. are setforth in Table 33 below. TABLE 33 Glycerin Total Impurities 25° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero (7D-i) 1% 100.00 0.020.65 0.56 3.90 (7D-ii) 0.2% 100.00 0.01 0.51 0.52 3.70 (7D-iii) 0.1%100.00 0.02 0.63 0.58 3.81 (7D-iv) 100.00 0.01 0.59 0.49 3.96 0.02%(7D-v) 100.00 0.02 0.54 0.52 3.95 0.002% 3 (7D-i) 1% 86.82 1.22 0.950.47 12.02 8.12 Months (7D-ii) 0.2% 46.83 6.13 2.56 0.60 46.56 42.86(7D-iii) 0.1% 87.07 1.52 1.03 0.49 14.56 10.75 (7D-iv) 59.19 4.64 1.780.69 36.18 32.22 0.02% (7D-v) 85.32 1.28 0.87 0.55 16.58 12.63 0.002% 6(7D-i) 1% 87.53 0.79 1.38 0.53 15.46 11.56 Months (7D-ii) 0.2% 39.883.54 4.54 0.52 54.18 50.48 (7D-iii) 0.1% 86.05 0.89 1.53 0.52 17.7813.97 (7D-iv) 55.62 2.09 2.93 0.64 42.49 38.53 0.02% (7D-v) 86.58 0.831.08 0.56 17.89 13.94 0.002%

The results of stability testing of Examples 7D-i-7D-v at 40° C. are setforth in Table 34 below. TABLE 34 Glycerin Total Impurities 40° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero (7D-i) 1% 100.00 0.020.65 0.56 3.90 (7D-ii) 0.2% 100.00 0.01 0.51 0.52 3.70 (7D-iii) 0.1%100.00 0.02 0.63 0.58 3.81 (7D-iv) 100.00 0.01 0.59 0.49 3.96 0.02%(7D-v) 100.00 0.02 0.54 0.52 3.95 0.002% 1 (7D-i) 1% 76.38 2.55 1.060.54 23.03 19.13 Month (7D-ii) 0.2% 81.48 1.33 0.89 0.52 19.15 15.45(7D-iii) 0.1% 84.52 2.07 0.86 0.53 19.16 15.35 (7D-iv) 52.70 3.96 1.750.55 39.11 35.15 0.02% (7D-v) 50.42 4.35 1.96 0.58 43.47 39.52 0.002% 2(7D-i) 1% 64.72 3.15 1.76 0.51 29.80 25.90 Months (7D-ii) 0.2% 70.281.29 1.43 0.62 25.47 21.77 (7D-iii) 0.1% 72.15 2.59 1.29 0.54 23.7719.96 (7D-iv) 45.57 3.31 3.04 0.60 44.34 40.38 0.02% (7D-v) 41.69 2.833.28 0.62 48.44 44.49 0.002% 3 (7D-i) 1% 50.17 3.34 3.39 0.62 39.2135.31 Months (7D-ii) 0.2% 62.28 1.60 2.69 0.55 31.48 27.78 (7D-iii) 0.1%63.00 3.08 2.41 0.57 29.94 26.13 (7D-iv) 37.61 3.27 5.02 0.68 51.8047.84 0.02% (7D-v) 34.82 5.44 5.35 0.73 54.47 50.52 0.002%

The results of stability testing of Examples 7D-i-7D-v at 55° C. are setforth in Table 35 below. TABLE 35 Glycerin Total Impurities 55° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero (7D-i) 1% 100.00 0.020.65 0.56 3.90 (7D-ii) 0.2% 100.00 0.01 0.51 0.52 3.70 (7D-iii) 0.1%100.00 0.02 0.63 0.58 3.81 (7D-iv) 100.00 0.01 0.59 0.49 3.96 0.02%(7D-v) 100.00 0.02 0.54 0.52 3.95 0.002% 1 (7D-i) 1% 86.50 0.01 0.790.48 15.02 11.12 Week (7D-ii) 0.2% 92.73 0.01 0.72 0.51 13.58 9.88(7D-iii) 0.1% 90.61 0.01 0.79 0.52 12.90 9.09 (7D-iv) 88.88 0.02 0.710.49 15.10 11.14 0.02% (7D-v) 88.77 0.02 0.80 0.49 16.67 12.72 0.002% 2(7D-i) 1% 42.43 0.06 3.04 0.48 48.24 44.34 Weeks (7D-ii) 0.2% 46.43 0.042.66 0.45 44.57 40.87 (7D-iii) 0.1% 42.78 0.04 3.14 0.58 48.10 44.29(7D-iv) 38.99 0.03 3.01 0.48 51.96 48.00 0.02% (7D-v) 37.79 0.04 3.080.44 52.66 48.71 0.002%

EXAMPLE 7E Dronabinol Solution in Sesame Oil Sourced from Croda, withVarying Amounts of Glycerin Added

In Example 7E, the effect of added varying amounts glycerin indronabinol formulation using sesame oil sourced from Croda wasevaluated. In each of Examples 7E-i-7E-v, the specified amount ofglycerin added was prepared in accordance with Example 7. Theformulations were then used to fill amber glass vials. The formulationswithin the vials were initially tested, then tested at 25° C. for 3 and6 months; 40° C. for 1, 2 and 3 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Examples 7E-i-7E-v at 25° C. are setforth in Table 36 below. TABLE 36 Glycerin Total Impurities 25° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero (7E-i) 1% 100.00 0.030.50 0.59 3.79 (7E-ii) 0.2% 100.00 0.01 0.49 0.61 4.09 (7E-iii) 0.1%100.00 0..01 0.47 0.60 4.00 (7E-iv) 100.00 0.02 0.50 0.60 3.90 0.02%(7E-v) 100.00 0.02 0.49 0.60 4.12 0.002% 3 (7E-i) 1% 70.63 4.29 1.040.53 28.37 24.58 Months (7E-ii) 0.2% 68.17 4.50 1.19 0.52 31.50 27.41(7E-iii) 0.1% 71.77 3.91 1.01 0.53 27.43 23.43 (7E-iv) 60.35 4.64 1.260.57 36.57 32.67 0.02% (7E-v) 53.20 5.40 1.37 0.58 42.71 38.59 0.002% 6(7E-i) 1% 63.43 4.19 1.42 0.65 33.77 29.98 Months (7E-ii) 0.2% 58.494.63 1.54 0.60 38.65 34.56 (7E-iii) 0.1% 63.93 5.32 1.48 0.62 36.2132.21 (7E-iv) 53.03 4.39 1.55 0.65 42.48 38.58 0.02% (7E-v) 45.00 4.591.80 0.63 48.57 44.45 0.002%

The results of stability testing of Examples 7E-i-7E-v at 40° C. are setforth in Table 37 below. TABLE 37 Glycerin Total Impurities 40° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero (7E-i) 1% 100.00 0.030.50 0.59 3.79 (7E-ii) 0.2% 100.00 0.01 0.49 0.61 4.09 (7E-iii) 0.1%100.00 0..01 0.47 0.60 4.00 (7E-iv) 100.00 0.02 0.50 0.60 3.90 0.02%(7E-v) 100.00 0.02 0.49 0.60 4.12 0.002% 1 (7E-i) 1% 48.72 5.38 1.740.64 47.55 43.76 Month (7E-ii) 0.2% 82.25 2.53 0.70 0.56 19.99 15.90(7E-iii) 0.1% 26.31 6.36 2.29 0.50 66.51 62.51 (7E-iv) 71.91 3.89 0.970.54 29.67 25.77 0.02% (7E-v) 84.93 1.97 0.66 0.54 17.91 13.79 0.002% 2(7E-i) 1% 37.99 4.44 2.73 0.61 48.50 44.71 Months (7E-ii) 0.2% 70.503.45 0.98 0.56 25.86 21.77 (7E-iii) 0.1% 18.12 5.13 4.06 0.62 73.0969.09 (7E-iv) 59.49 4.38 1.37 0.55 34.19 30.29 0.02% (7E-v) 74.54 2.690.87 0.61 22.82 18.70 0.002% 3 (7E-i) 1% 27.98 4.07 5.18 0.94 57.6253.83 Months (7E-ii) 0.2% 59.94 3.81 1.80 0.58 32.85 28.76 (7E-iii) 0.1%13.43 5.45 7.33 1.12 76.80 72.80 (7E-iv) 49.87 4.41 2.48 0.57 38.9335.03 0.02% (7E-v) 66.48 3.26 1.48 0.54 28.45 24.33 0.002%

The results of stability testing of Examples 7E-i-7E-v at 55° C. are setforth in Table 38 below. TABLE 38 Glycerin Total Impurities 55° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero (7E-i) 1% 100.00 0.030.50 0.59 3.79 (7E-ii) 0.2% 100.00 0.01 0.49 0.61 4.09 (7E-iii) 0.1%100.00 0..01 0.47 0.60 4.00 (7E-iv) 100.00 0.02 0.50 0.60 3.90 0.02%(7E-v) 100.00 0.02 0.49 0.60 4.12 0.002% 1 (7E-i) 1% 84.97 0.01 0.750.56 15.42 11.63 Week (7E-ii) 0.2% 86.55 0.05 0.71 0.57 18.20 14.11(7E-iii) 0.1% 84.25 0.10 0.76 0.52 20.65 16.63 (7E-iv) 86.91 0.08 0.660.55 17.86 13.96 0.02% (7E-v) 84.44 0.11 0.76 0.53 20.93 16.81 0.002% 2(7E-i) 1% 67.98 0.01 1.78 0.55 24.93 21.14 Weeks (7E-ii) 0.2% 26.76 0.182.76 0.71 65.03 60.94 (7E-iii) 0.1% 65.98 0.19 1.42 0.54 33.00 29.00(7E-iv) 21.93 0.34 3.26 0.64 71.79 67.89 0.02% (7E-v) 19.08 0.14 3.660.67 72.97 68.85 0.002%

EXAMPLE 7F Dronabinol Solution in Sesame Oil Sourced from Dipasa, withVarying Amounts of Glycerin Added

In Example 7F, the effect of added varying amounts glycerin indronabinol formulation using sesame oil sourced from Dipasa wasevaluated. In each of Examples 7F-i-7F-v, the specified amount ofglycerin added was prepared in accordance with Example 7. Theformulations were then used to fill amber glass vials. The formulationswithin the vials were initially tested, then tested at 25° C. for 3 and6 months; 40° C. for 1, 2 and 3 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Examples 7F-i-7F-v at 25° C. are setforth in Table 39 below. TABLE 39 Glycerin Total Impurities 25° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero (7F-i) 1% 100.00 0.030.56 0.63 3.99 (7F-ii) 0.2% 100.00 0.01 0.66 0.57 3.99 (7F-iii) 0.1%100.00 0.01 0.55 0.60 4.04 (7F-iv) 100.00 0.03 0.54 0.57 4.05 0.02%(7F-v) 100.00 0.01 0.54 0.56 3.89 0.002% 3 (7F-i) 1% 94.38 0.34 0.690.53 9.98 5.99 Months (7F-ii) 0.2% 94.84 0.31 0.70 0.52 6.11 2.12(7F-iii) 0.1% 95.13 0.26 0.71 0.52 5.95 1.91 (7F-iv) 95.21 0.25 0.700.53 7.22 3.17 0.02% (7F-v) 95.13 0.26 0.73 0.62 7.36 3.47 0.002% 6(7F-i) 1% 96.00 0.29 0.93 0.57 8.56 4.57 Months (7F-ii) 0.2% 96.56 0.270.94 0.55 8.54 4.55 (7F-iii) 0.1% 97.72 0.28 0.93 0.55 8.77 4.73 (7F-iv)96.81 0.32 0.93 0.55 8.96 4.91 0.02% (7F-v) 96.66 0.29 0.93 0.54 8.945.05 0.002%

The results of stability testing of Examples 7F-i-7F-v at 40° C. are setforth in Table 40 below. TABLE 40 Glycerin Total Impurities 40° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero (7F-i) 1% 100.00 0.030.56 0.63 3.99 (7F-ii) 0.2% 100.00 0.01 0.66 0.57 3.99 (7F-iii) 0.1%100.00 0.01 0.55 0.60 4.04 (7F-iv) 100.00 0.03 0.54 0.57 4.05 0.02%(7F-v) 100.00 0.01 0.54 0.56 3.89 0.002% 1 (7F-i) 1% 93.29 0.16 0.710.57 7.27 3.28 Month (7F-ii) 0.2% 95.22 0.16 0.72 0.58 7.39 3.40(7F-iii) 0.1% 96.08 0.13 0.71 0.56 7.26 3.22 (7F-iv) 97.10 0.13 0.720.57 7.28 3.23 0.02% (7F-v) 97.38 0.16 0.73 0.56 7.28 3.39 0.002% 2(7F-i) 1% 90.45 0.26 1.05 0.61 10.59 6.60 Months (7F-ii) 0.2% 92.16 0.251.08 0.56 10.37 6.38 (7F-iii) 0.1% 91.19 0.44 1.03 0.55 11.00 6.96(7F-iv) 90.74 0.23 1.05 0.56 10.82 6.77 0.02% (7F-v) 90.76 0.23 1.060.57 10.71 6.82 0.002% 3 (7F-i) 1% 85.37 0.32 1.77 0.59 14.68 10.69Months (7F-ii) 0.2% 87.97 0.34 1.83 0.55 13.84 9.85 (7F-iii) 0.1% 88.240.41 1.73 0.58 13.91 9.87 (7F-iv) 86.30 0.42 1.75 0.56 14.61 10.56 0.02%(7F-v) 86.80 0.58 1.75 0.54 14.97 11.08 0.002%

The results of stability testing of Examples 7F-i-7F-v at 55° C. are setforth in Table 41 below. TABLE 41 Glycerin Total Impurities 55° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero (7F-i) 1% 100.00 0.030.56 0.63 3.99 (7F-ii) 0.2% 100.00 0.01 0.66 0.57 3.99 (7F-iii) 0.1%100.00 0.01 0.55 0.60 4.04 (7F-iv) 100.00 0.03 0.54 0.57 4.05 0.02%(7F-v) 100.00 0.01 0.54 0.56 3.89 0.002% 1 (7F-i) 1% 96.81 0.02 0.720.53 6.99 3.00 Week (7F-ii) 0.2% 98.85 0.04 0.75 0.55 7.23 3.24 (7F-iii)0.1% 98.53 0.03 0.80 0.55 7.32 3.28 (7F-iv) 97.55 0.04 0.82 0.58 7.833.78 0.02% (7F-v) 96.92 0.04 0.54 0.56 7.88 3.99 0.002% 2 (7F-i) 1%93.18 0.01 0.99 0.60 9.38 5.39 Weeks (7F-ii) 0.2% 92.04 0.01 1.09 0.539.64 5.65 (7F-iii) 0.1% 92.80 0.01 1.12 0.57 10.48 6.44 (7F-iv) 91.550.01 1.20 0.57 10.75 6.70 0.02% (7F-v) 89.74 0.01 1.31 0.52 11.18 7.290.002%

As can be seen from the results above, the addition of glycerin makesdronabinol highly unstable. The amount of dronabinol chemically degradedis proportional to the glycerin concentration added. Dronabinoldegradation continued with increase in storage period. However,dronabinol in sesame oil sourced from Dipasa is highly resistant todegradation induced by glycerin. This stability is believed to be due tothe high antioxidant content in sesame oil sourced from Dipasa, mostnotably lecithin.

EXAMPLE 8 Stability Studies

The International Conference on Harmonisation (ICH) of TechnicalRequirements for Registration of Pharmaceuticals for Human Use (ICH) hasadopted scientific standards for stability testing. These standards arethe basis of regulatory guidances published by the FDA (Guidance forIndustry, Q1A). The purpose of stability tests is to provide evidence onhow the quality and safety of the product varies with time. As per theFDA guidance, a finished product is assigned a tentative two-yearexpiration dating at room temperature (25° C.) if the product is stablefor 6 months at accelerated testing conditions, 40° C. (15° C. above thedesignated long-term storage temperature). In Example 8, a dronabinolformulation in sesame oil (super-refined, from Croda) was prepared inaccordance with Example 1, and packaged in a round, amber glass bottle,which are stored at elevated temperature and humidity levels, 40° C./75%relative humidity (RH) to demonstrate stability of the formulation atroom temperature. The formulation was also tested at 2-8° C., 25° C./60%relative humidity and 30° C./60% relative humidity.

The concentrations of dronabinol and the impurities/degradants [D8THC,Cannabidiol (CDN) and Cannabidiol (CBD)] are determined by using thecompendial (USP) HPLC method after storage for pre-determined timeperiods and conditions as set forth in Table 42. The results of thestability testing of Example 8 are set forth in Table 42 below. TABLE 42Related Substances (GC) Time Assay Delta- Condition (Months) (HPLC)8-THC CBN CBD Dissolution Test Initial 0 101.40% 0.90% 1.30% 0.20% NMT 5min 2-8° C. 1 98.40% 0.90% 0.70% ND NMT 2 min 2 98.30% 0.70% 1.00% NDNMT 1 min 3 99.80% 0.70% 1.00% ND NMT 1 min 6 101.30% 1.10% 1.00% ND NMT1 min 25° C./60% RH 1 99.00% 0.70% 0.70% ND NMT 2 min 2 98.40% 0.70%1.10% ND NMT 1 min 3 98.60% 0.70% 1.10% ND NMT 1 min 6 96.40% 1.20%1.20% ND NMT 1 min 30° C./60% RH 1 98.50% 0.90% 0.60% ND NMT 3 min 297.00% 0.70% 1.20% ND NMT 1 min 3 98.50% 0.70% 1.00% ND NMT 2 min 698.20% 1.30% 1.20% ND NMT 3 min 40° C./75% RH 0.5 100.00% 0.60% 0.80% NDNMT 3 min 1 97.00% 1.00% 0.70% ND NMT 4 min 2 96.90% 0.70% 1.20% ND NMT1 min 3 92.80% 0.80% 1.40% ND NMT 1 min 6 94.00% 1.40% 1.70% ND NMT 3minND = not detectedNMT = not more thanGC = gas chromatography

The above stability studies are believed to demonstrate that by removingglycerin/glycerol, a dronabinol oral drug product that is stable for twoyears at room temperature is obtained.

It is hypothesized that hard gelatin capsule shells do not containglycerol and therefore a major cause of instability for the activepharmaceutical ingredient dronabinol is eliminated (as compared to thereference standard product, Marinol, which is encapsulated in softgelatin capsules). Also, by utilizing hard gelatin capsules toencapsulate dronabinol solution, the need for plasticizer (glycerin) iseliminated.

EXAMPLE 9 Effect of Different Brands of Sesame Oil on Stability

In order to study of the effect of the type and source of sesame oil onthe stability of the active ingredient dronabinol, different sources ofsesame oil were obtained from the following vendors: Super Refined NFgrade from Croda; NF grade from Arista & Dipasa; and food grade fromColumbus. Formulations of active ingredient (dronabinol) in varyingamounts and sesame oil were prepared according the method described inExample 1.

Example 9-i is a 5 mg dronabinol (3.03% w/w) solution in sesame oil, NF(by Arista).

Example 9-ii is a 5 mg dronabinol (3.03% w/w) solution in sesame oil(super refined NF, by Croda).

Example 9-iii is a 10 mg dronabinol (6.06% w/w) solution in sesame oil,NF (from Dipasa).

Example 9-iv is a 10 mg dronabinol (6.06% w/w) solution in food gradesesame oil (obtained from Columbus).

A summary of the compositions of Examples 9-i-9-iv is set forth in Table43 below: TABLE 43 Composition Sesame Formulation No. Dronabinol OilOther Ingredients Example 9-i (Arista) 3.03% w/w QS — Example 9-ii(Croda) 3.03% w/w QS — Example 9-iii (Dipasa) 6.06% w/w QS — Example9-iv (Columbus) 6.06% w/w QS —

The formulations were stored in amber glass vials at 55° C. while beingtested for stability under elevated temperature conditions (initially(“zero time”), 55° for one week and two weeks, respectively). Theresults shown are presented in Table 44. TABLE 44 TOTAL RELATEDSUBSTANCES CONDITION FORMULATION # ASSAY % IMPURITY % D8THC % CBN % CBD% Zero Time Example 9-i 96.59 3.41 0.48 0.51 — (Arista) Example 9-ii93.80 6.20 0.75 1.88 0.29 (Croda) Example 9-iii 94.60 3.78 0.42 0.600.09 (Dipasa) Example 9-iv 94.97 3.35 0.44 0.49 0.02 (Columbus) 55° C.Example 9-i 94.50 5.50 0.46 0.64 0.30 (1 week) (Arista) Example 9-ii82.16 17.84 0.72 1.86 0.23 (Croda) Example 9-iii 94.29 5.71 0.42 1.110.20 (Dipasa) Example 9-iv 87.55 12.45 0.51 1.83 0.48 (Columbus) 55° C.Example 9-i 92.75 7.25 0.52 0.64 0.58 (2 weeks) (Arista) Example 9-ii67.41 32.59 1.06 4.96 0.29 (Croda) Example 9-iii 92.92 7.08 0.52 1.540.05 (Dipasa) Example 9-iv 71.32 28.68 0.60 3.78 0.27 (Columbus)

Based on the results set forth in Table 44 above, the type (and source)of sesame oil used plays a major role in stabilizing the activeingredient dronabinol. Dronabinol formulations prepared from NF gradesesame oil sourced from Dipasa showed increased stability when comparedto similar formulations prepared from NF grade sourced sesame oil fromCroda and Arista and food grade sesame oil sourced from Columbus.

Extended Stability Results—Effect of Different Brands of Sesame Oil onStability

It was believed that the source of sesame oil used in the dronabinolformulation is important to the stability of the formulation. To confirmwhether the lack of sufficient antioxidants in certain brands of sesameoil caused a lack of stability and an increase in dronabinol relatedimpurities such as delta-8-THC, CBD and CBN, stability studies at roomtemperature and at accelerated conditions over an extended period oftime were conducted using sesame oil from Arista, Croda and Dipasa.

EXAMPLE 9A Effect of Arista Brand Sesame Oil on Stability

In Example 9A, the effect of the Arista brand of sesame oil used in thedronabinol formulation was evaluated. The formulation was prepared inaccordance with the method described for Example 9-i. The formulationwas then used to fill hard gelatin capsules in accordance with Example2. The formulation within the capsules was initially tested, then testedat 25° C. for 3 and 6 months; 40° C. for 1, 2 and 3 months and at 55° C.for 1 and 2 weeks.

The results of stability testing of Examples 9A at 25° C. are set forthin Table 45 below. TABLE 45 Control CBD CBN Total Impurities 25° C.Potency % % % D8-THC % % Increase + % Zero 100.00 0.08 0.50 0.57 4.36 3Months 91.72 0.31 0.84 0.49 11.16 6.80 6 Months 92.71 1.01 1.16 0.4711.16 6.80

The results of stability testing of Examples 9A at 40° C. are set forthin Table 46 below. TABLE 46 Control CBD CBN Total Impurities 40° C.Potency % % % D8-THC % % Increase + % Zero 100.00 0.08 0.50 0.57 4.36 1Month 95.18 0.59 0.74 0.48 9.86 5.50 2 Months 93.22 0.43 0.88 0.52 10.416.05 3 Months 91.36 0.53 1.16 0.51 10.98 6.62

The results of stability testing of Examples 9A at 55° C. are set forthin Table 47 below. TABLE 47 Control CBD CBN Total Impurities 55° C.Potency % % % D8-THC % % Increase + % Zero 100.00 0.08 0.50 0.57 4.36 1Week 90.42 0.08 0.68 0.48 13.06 8.70 2 Weeks 44.67 0.02 2.63 0.56 47.4543.09

In Example 9B, the effect of the Croda brand of sesame oil used in thedronabinol formulation was evaluated. The formulation was prepared inaccordance with the method described for Example 9-ii. The formulationwas then used to fill hard gelatin capsules in accordance with Example2. The formulation within the capsules was initially tested, then testedat 25° C. for 3 and 6 months; 40° C. for 1, 2 and 3 months and at 55° C.for 1 and 2 weeks.

The results of stability testing of Examples 9B at 25° C. are set forthin Table 48 below. TABLE 48 Control CBD CBN Total Impurities 25° C.Potency % % % D8-THC % % Increase + % Zero 100.00 0.08 0.46 0.59 4.13 3Months 87.36 0.32 0.62 0.62 13.61 9.48 6 Months 91.63 1.33 0.78 0.4914.87 10.74

The results of stability testing of Examples 9B at 40° C. are set forthin Table 49 below. TABLE 49 Control CBD CBN Total Impurities 40° C.Potency % % % D8-THC % % Increase + % Zero 100.00 0.08 0.46 0.59 4.13 1Month 91.25 0.97 0.62 0.53 12.18 8.05 2 Months 87.59 0.81 0.71 0.5713.03 8.90 3 Months 87.62 1.02 0.90 0.56 13.78 9.65

The results of stability testing of Examples 9B at 55° C. are set forthin Table 50 below. TABLE 50 Control CBD CBN Total Impurities 55° C.Potency % % % D8-THC % % Increase + % Zero 100.00 0.08 0.46 0.59 4.13 1Week 85.53 0.09 0.69 0.51 15.38 11.25 2 Weeks 38.10 0.20 2.72 0.57 57.4053.27

EXAMPLE 9C Effect of Dipasa Brand Sesame Oil on Stability

In Example 9C, the effect of the Dipasa brand of sesame oil used in thedronabinol formulation was evaluated. The formulation was prepared inaccordance with the method described for Example 9-iii, with adronabinol concentration of 3.03%. The formulation was then used to fillhard gelatin capsules in accordance with Example 2. The formulationwithin the capsules was initially tested, then tested at 25° C. for 3and 6 months; 40° C. for 1, 2 and 3 months and at 55° C. for 1 and 2weeks.

The results of stability testing of Examples 9C at 25° C. are set forthin Table 51 below. TABLE 51 Control CBD CBN Total Impurities 25° C.Potency % % % D8-THC % % Increase + % Zero 100.00 0.02 0.51 0.57 3.96 3Months 95.72 0.05 0.68 0.45 5.41 1.45 6 Months 98.00 0.38 0.76 0.55 8.494.53

The results of stability testing of Examples 9C at 40° C. are set forthin Table 52 below. TABLE 52 Control CBD CBN Total Impurities 40° C.Potency % % % D8-THC % % Increase + % Zero 100.00 0.02 0.51 0.57 3.96 1Month 97.56 0.16 0.67 0.55 6.63 2.67 2 Months 92.49 0.20 0.96 0.56 10.156.19 3 Months 90.02 0.41 1.50 0.53 12.29 8.33

The results of stability testing of Examples 9C at 55° C. are set forthin Table 53 below. TABLE 53 Control CBD CBN Total Impurities 55° C.Potency % % % D8-THC % % Increase + % Zero 100.00 0.02 0.51 0.57 3.96 1Week 97.60 0.11 0.82 0.54 6.94 2.98 2 Weeks 96.17 0.12 1.14 0.54 9.455.49

EXAMPLE 9D Effect of Arista Brand Sesame Oil on Stability—Vials

In Example 9D, the effect of the Arista brand of sesame oil used in thedronabinol formulation was evaluated. The formulation was prepared inaccordance with the method described for Example 9-i. The formulationwas then used to fill amber glass vials. The formulation within thevials was initially tested, then tested at 25° C. for 3 and 6 months;40° C. for 1, 2 and 3 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Examples 9D at 25° C. are set forthin Table 54 below. TABLE 54 Control CBD CBN Total Impurities 25° C.Potency % % % D8-THC % % Increase + % Zero 100.00 0.08 0.50 0.57 4.36 3Months 96.92 0.25 0.55 0.55 6.91 2.55 6 Months 99.65 0.14 0.60 0.51 7.493.13

The results of stability testing of Examples 9D at 40° C. are set forthin Table 55 below. TABLE 55 Control D8- Total Impurities 40° C. Potency% CBD % CBN % THC % % Increase + % Zero 100.00 0.08 0.50 0.57 4.36 1Month 98.42 0.06 0.51 0.49 5.79 1.43 2 Months 95.26 0.10 0.59 0.49 9.505.14 3 Months 90.41 0.64 0.90 0.49 13.67 9.31

The results of stability testing of Examples 9D at 55° C. are set forthin Table 56 below. TABLE 56 Control D8- Total Impurities 55° C. Potency% CBD % CBN % THC % % Increase + % Zero 100.00 0.08 0.50 0.57 4.36 1Week 90.42 0.08 0.68 0.48 13.06 8.70 2 Weeks 44.67 0.02 2.63 0.56 47.4543.09

EXAMPLE 9E Effect of Croda Brand Sesame Oil on Stability—Vials

In Example 9E, the effect of the Croda brand of sesame oil used in thedronabinol formulation was evaluated. The formulation was prepared inaccordance with the method described for Example 9-ii. The formulationwas then used to fill amber glass vials. The formulation within thevials was initially tested, then tested at 25° C. for 3 and 6 months;40° C. for 1, 2 and 3 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Examples 9E at 25° C. are set forthin Table 57 below. TABLE 57 Control D8- Total Impurities 25° C. Potency% CBD % CBN % THC % % Increase + % Zero 100.00 0.08 0.46 0.59 4.13 3Months 71.55 3.62 1.26 0.56 28.72 24.59 6 Months 61.65 4.36 1.96 0.6840.12 35.99

The results of stability testing of Examples 9E at 40° C. are set forthin Table 58 below. TABLE 58 Control D8- Total Impurities 40° C. Potency% CBD % CBN % THC % % Increase + % Zero 100.00 0.08 0.46 0.59 4.13 1Month 80.41 3.21 0.98 0.52 23.01 18.88 2 Months 71.75 3.76 1.14 0.4828.08 23.95 3 Months 60.30 4.21 1.94 0.58 34.99 30.86

The results of stability testing of Examples 9E at 55° C. are set forthin Table 59 below. TABLE 59 Control D8- Total Impurities 55° C. Potency% CBD % CBN % THC % % Increase + % Zero 100.00 0.08 0.46 0.59 4.13 1Week 85.53 0.09 0.69 0.51 15.38 11.25 2 Weeks 38.10 0.20 2.72 0.57 57.4053.27

EXAMPLE 9F Effect of Dipasa Brand Sesame Oil on Stability—Vials

In Example 9F, the effect of the Dipasa brand of sesame oil used in thedronabinol formulation was evaluated. The formulation was prepared inaccordance with the method described for Example 9-iii. The formulationwas then used to fill amber glass vials. The formulation within thevials was then tested at 25° C. for 3 and 6 months; 40° C. for 1, 2 and3 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Examples 9F at 25° C. are set forthin Table 60 below. TABLE 60 Control D8- Total Impurities 25° C. Potency% CBD % CBN % THC % % Increase + % Zero 100.00 0.02 0.51 0.57 3.96 3Months 96.39 0.25 0.70 0.60 7.26 3.30 6 Months 98.27 0.23 0.92 0.60 8.414.45

The results of stability testing of Examples 9F at 40° C. are set forthin Table 61 below. TABLE 61 Control D8- Total Impurities 40° C. Potency% CBD % CBN % THC % % Increase + % Zero 100.00 0.02 0.51 0.57 3.96 1Month 96.49 0.12 0.75 0.53 6.50 2.54 2 Months 92.98 0.22 1.07 0.55 10.226.26 3 Months 88.64 0.43 1.70 0.55 14.19 10.23

The results of stability testing of Examples 9F at 55° C. are set forthin Table 62 below. TABLE 62 Control D8- Total Impurities 55° C. Potency% CBD % CBN % THC % % Increase + % Zero 100.00 0.02 0.51 0.57 3.96 1Week 97.60 0.11 0.82 0.54 6.94 2.98 2 Weeks 96.17 0.12 1.14 0.54 9.455.49

Based on the results set forth in above tables, it is clear that thesource of sesame oil plays a vital role towards the stability ofdronabinol formulations.

Formulations containing NF grade sesame oil from Arista and Dipasashowed greater stability than super refined sesame oil from Croda.

EXAMPLE 10 HPLC Analysis of Formulation 9-iii

In Example 10, the dronabinol solution of Example 9-iii was furtheranalyzed. In Example 10a, the formulation of Example 9-iii was stored at55° C. for two weeks and then subjected to HPLC analysis. The resultsare provided in FIG. 1.

Chromatograms obtained by the High Performance Liquid Chromatography(HPLC) analysis of dronabinol drug product stability samples show a peakat approximately 4.4 minutes which corresponds to sesamin, a majoranti-oxidant in sesame oil (FIG. 1).

This presence of sesamin was confirmed by spiking the sample solutionwith sesamin. In particular, in Example 10b, the formulation of Example9-iii was spiked with 1% w/w sesamin (purity: >95%) obtained fromIndustrial Research Ltd., Lower Hutt, New Zealand. The formulation ofExample 10b was stored at 55° C. for two weeks and then subjected toHPLC analysis. The results are provided in FIG. 2.

Most impurities including all the sesame oil anti-oxidants are removedduring the purification of NF grade to super refined NF grade sesame oil(Super Refined Oils PN-25, Croda Inc., Data Sheet, hereby incorporatedby reference). Therefore, the instability of dronabinol formulationsprepared using super refined sesame oil sourced from Croda may beattributed to the absence of anti-oxidants, sesamin in specific. Thespecifications of the sesame oil obtained from various vendors (Arista,Dipasa, Croda, Columbus) revealed that sesamin was present only in Foodand NF grade sesame oils but not in the super refined sesame oil sourcedfrom Croda.

EXAMPLE 11 Stability Results—Addition of Free Fatty Acid(s)

The instability of dronabinol formulations prepared using food gradesesame oil led us to investigate further the effects of other impuritiesin sesame oil (including free fatty acid on dronabinol formulations).Sesame oil contains one or more free fatty acids, of which myristic acidis prominent (Beckstrom-Sternberg et al., 1994). In order to examinewhether the presence of acids oxidize dronabinol, the effect of addedfatty acid in dronabinol formulated as a sesame oil solution wasevaluated. In Example 11, the specified amount of fatty acid was addedto formulations prepared in accordance with Example 1.

Example 11-i is a solution of 5 mg dronabinol (3.03%) and 0.5% myristicacid in sesame oil, NF (by Arista).

Example 11-ii is a solution of 5 mg dronabinol (3.03%) and 0.1% myristicacid in sesame oil, NF (by Arista).

Example 11-iii is a solution of 5 mg dronabinol (3.03%) and 0.05%myristic acid in sesame oil, NF (by Arista).

Example 11-iv is a solution of 5 mg dronabinol (3.03%) and 0.007%myristic acid in sesame oil, NF (by Arista).

Example 11-v is a solution of 5 mg dronabinol (3.03%) and 0.5% myristicacid in sesame oil, super refined NF (by Croda).

Example 11-vi is a solution of 5 mg dronabinol (3.03%) and 0.1% myristicacid in sesame oil, super refined NF (by Croda).

Example 11-vii is a solution of 5 mg dronabinol (3.03%) and 0.05%myristic acid in sesame oil, super refined NF (by Croda).

Example 11-viii is a solution of 5 mg dronabinol (3.03%) and 0.007%myristic acid in sesame oil, super refined NF (by Croda).

A summary of the compositions of Examples 11-i-11-viii is set forth inTable 63 below: TABLE 63 Composition Sesame Formulation No. DronabinolOil Other Ingredients Example 11-i 3.03% w/w QS Myristic Acid (0.5%)Example 11-ii 3.03% w/w QS Myristic Acid (0.1%) Example 11-iii 3.03% w/wQS Myristic Acid (0.05%) Example 11-iv 3.03% w/w QS Myristic Acid(0.007%) Example 11-v 3.03% w/w QS Myristic Acid (0.5%) Example 11-vi3.03% w/w QS Myristic Acid (0.1%) Example 11-vii 3.03% w/w QS MyristicAcid (0.05%) Example 11-viii 3.03% w/w QS Myristic Acid (0.007%)

The formulations were tested for stability while stored in amber glassvials at 55° C. for one week (Table 64) and two weeks (Table 65),respectively. TABLE 64 RELATED TOTAL SUBSTANCES ASSAY IMPURITY D8THC CBNCBD FORMULATION* # % % % % % Example 11-i 92.15 7.85 0.55 1.81 0.27 (A +mysristic0.5%) Example 11-iii 92.83 7.17 0.48 1.38 0.31 (A +mysristic0.05%) Example 11-vi 81.82 18.18 0.52 4.77 2.50 (C +mysristic0.1%) Example 11-viii 86.33 13.67 0.57 2.15 2.16 (C +mysristic0.007%)*A = Arista, C = Croda

TABLE 65 RELATED TOTAL SUBSTANCES ASSAY IMPURITY D8THC CBN CBDFORMULATION* # % % % % % Example 11-i 88.96 11.04 0.71 3.30 0.27 (A +mysristic0.5%) Example 11-iii 90.51 9.49 0.55 2.35 0.09 (A +mysristic0.05%) Example 11-vi 68.61 31.39 0.91 8.26 0.18 (C +mysristic0.1%) Example 11-viii 78.81 21.19 0.71 3.46 0.52 (C +mysristic0.007%)*A = Arista, C = Croda

As can be seen from the results set forth in Tables 64 and 65, theaddition of myristic acid to dronabinol formulation resulted indegradation of the active ingredient dronabinol. The results may also beexplained in whole or in part by the fact that the super-refined sesameoil from Croda has no sesamin.

Extended Stability Results—Addition of Free Fatty Acid(s)

To confirm whether the addition of the free fatty acid myristic acid ondronabinol formulations caused a lack of stability and an increase indronabinol related impurities such as delta-8-THC, CBD and CBN,stability studies at room temperature and at accelerated conditions overan extended period of time were conducted using sesame oil from Arista,Croda and Dipasa.

EXAMPLE 11A Dronabinol Solution in Sesame Oil Sourced fromArista—Capsules

In Example 11A, dronabinol formulations 11A-i and 11A-ii were preparedin accordance with Examples 11-i and 11-ii using sesame oil sourced fromArista. Formulation 11A-i contained 0.5% myristic acid and formulation11A-ii contained 0.1% myristic acid. The dronabinol formulations werethen used to fill hard gelatin capsules in accordance with Example 2.The formulations within the capsules were initially tested, then testedat 25° C. for 3 and 6 months; 40° C. for 1, 2 and 3 months and at 55° C.for 1 and 2 weeks.

The results of stability testing of Example 11A-i-ii at 25° C. are setforth in Table 66 below. TABLE 66 Myristic acid Total Impurities 25° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 11A-i 0.5% 100.000.03 0.52 0.50 3.95 11A-ii 0.1% 100.00 0.02 0.49 0.51 3.91 3 11A-i 0.5%94.03 0.29 0.78 0.50 5.25 1.30 Months 11A-ii 0.1% 88.57 0.18 1.14 0.5010.68 6.77 6 11A-i 0.5% 94.86 0.32 1.14 0.50 6.95 3.00 Months 11A-ii0.1% 88.32 0.93 1.58 0.57 12.19 8.28

The results of stability testing of Example 11A-i-ii at 40° C. are setforth in Table 67 below. TABLE 67 Myristic acid Total Impurities 40° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 11A-i 0.5% 100.000.03 0.52 0.50 3.95 11A-ii 0.1% 100.00 0.02 0.49 0.51 3.91 1 11A-i 0.5%90.98 0.18 1.83 0.49 10.36 6.41 Month 11A-ii 0.1% 88.24 0.32 1.37 0.4810.56 6.65 2 11A-i 0.5% 88.26 0.13 1.94 0.51 11.72 7.77 Months 11A-ii0.1% 86.99 0.22 1.61 0.42 11.70 7.79 3 11A-i 0.5% 86.96 0.28 2.36 0.4512.74 8.79 Months 11A-ii 0.1% 84.92 0.35 1.98 0.50 12.40 8.49

The results of stability testing of Example 11A-i-ii at 55° C. are setforth in Table 68 below. TABLE 68 Myristic acid Total Impurities 55° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 11A-i 0.5% 100.000.03 0.52 0.50 3.95 11A-ii 0.1% 100.00 0.02 0.49 0.51 3.91 1 11A-i 0.5%91.53 0.03 1.53 0.59 10.33 6.38 Week 11A-ii 0.1% 87.94 0.01 0.92 0.4913.11 9.20 2 11A-i 0.5% 88.83 0.01 2.10 0.55 12.76 8.81 Weeks 11A-ii0.1% 71.58 0.03 2.16 0.58 23.69 19.78

EXAMPLE 11B Dronabinol Solution in Sesame Oil Sourced fromCroda—Capsules

In Example 11B, dronabinol formulations 11B-i and 11B-ii were preparedin accordance with Examples 11-v and 11-vi using sesame oil sourced fromCroda. Formulation 11B-i contained 0.5% myristic acid and formulation11A-ii contained 0.1% myristic acid. The dronabinol formulations werethen used to fill hard gelatin capsules in accordance with Example 2.The formulations within the capsules, were initially tested, then testedat 25° C. for 3 and 6 months; 40° C. for 1, 2 and 3 months and at 55° C.for 1 and 2 weeks.

The results of stability testing of Example 11B-i-ii at 25° C. are setforth in Table 69 below. TABLE 69 Myristic acid Total Impurities 25° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 11B-i 0.5% 100.000.03 0.48 0.65 5.69 11B-ii 0.1% 100.00 0.02 0.46 0.62 2.29 3 11B-i 0.5%89.16 0.17 1.93 0.56 11.08 5.39 Months 11B-ii 0.1% 89.25 0.21 0.99 0.5512.56 7.27 6 11B-i 0.5% 91.12 0.65 2.24 0.67 12.29 6.60 Months 11B-ii0.1% 91.66 1.34 1.44 0.53 14.19 8.90

The results of stability testing of Example 11B-i-ii at 40° C. are setforth in Table 70 below. TABLE 70 Myristic acid Total Impurities 40° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 11B-i 0.5% 100.000.03 0.48 0.65 5.69 11B-ii 0.1% 100.00 0.02 0.46 0.62 2.29 1 11B-i 0.5%62.73 1.00 8.49 0.97 31.26 25.57 Month 11B-ii 0.1% 91.93 0.84 1.16 0.6012.04 6.75 2 11B-i 0.5% 88.49 0.21 2.21 0.57 12.51 6.82 Months 11B-ii0.1% 87.83 0.49 1.45 0.62 13.49 8.20 3 11B-i 0.5% 85.11 0.34 2.82 0.5815.11 9.42 Months 11B-ii 0.1% 86.43 0.53 2.08 0.58 14.70 9.41

The results of stability testing of Example 11B-i-ii at 55° C. are setforth in Table 71 below. TABLE 71 Myristic acid Total Impurities 55° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 11B-i 0.5% 100.000.03 0.48 0.65 5.69 11B-ii 0.1% 100.00 0.02 0.46 0.62 2.29 1 11B-i 0.5%87.77 0.01 1.99 0.63 14.67 8.98 Week 11B-ii 0.1% 85.94 0.03 0.96 0.5217.11 11.82 2 11B-i 0.5% 46.26 0.05 10.13 1.16 45.43 39.74 Weeks 11B-ii0.1% 33.85 0.09 5.57 0.65 57.47 52.18

EXAMPLE 11C Dronabinol Solution in Sesame Oil Sourced fromDipasa—Capsules

In Example 11C, dronabinol formulations 11C-i and 11C-ii were preparedin accordance with Examples 11B-i and 11B-ii using sesame oil sourcedfrom Dipasa. Formulation 11C-i contained 0.5% myristic acid andformulation 11C-ii contained 0.1% myristic acid. The dronabinolformulations were then used to fill hard gelatin capsules in accordancewith Example 2. The formulations within the capsules were initiallytested, then tested at 25° C. for 3 and 6 months; 40° C. for 1, 2 and 3months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 11C-i-ii at 25° C. are setforth in Table 72 below. TABLE 72 Myristic acid Total Impurities 25° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 11C-i 0.5% 100.000.06 0.53 0.54 3.81 11C-ii 0.1% 100.00 0.02 0.56 0.60 3.96 3 11C-i 0.5%92.81 0.05 0.89 0.53 5.80 1.99 Months 11C-ii 0.1% 93.55 0.05 0.70 0.556.11 2.15 6 11C-i 0.5% 94.79 0.29 1.20 0.56 7.10 3.29 Months 11C-ii 0.1%93.80 0.43 0.98 0.52 7.90 3.94

The results of stability testing of Example 11C-i-ii at 40° C. are setforth in Table 73 below. TABLE 73 Myristic acid Total Impurities 40° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 11C-i 0.5% 100.000.06 0.53 0.54 3.81 11C-ii 0.1% 100.00 0.02 0.56 0.60 3.96 1 11C-i 0.5%92.08 0.18 1.29 0.54 9.05 5.24 Month 11C-ii 0.1% 92.91 0.22 0.86 0.628.06 4.10 2 11C-i 0.5% 88.81 0.09 1.65 0.56 10.53 6.72 Months 11C-ii0.1% 88.46 0.14 1.31 0.51 10.53 6.57 3 11C-i 0.5% 87.23 0.19 2.10 0.5512.07 8.26 Months 11C-ii 0.1% 87.21 0.25 1.71 0.53 12.17 8.21

The results of stability testing of Example 11C-i-ii at 55° C. are setforth in Table 74 below. TABLE 74 Myristic acid Total Impurities 55° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 11C-i 0.5% 100.000.06 0.53 0.54 3.81 11C-ii 0.1% 100.00 0.02 0.56 0.60 3.96 1 11C-i 0.5%97.34 0.01 0.81 0.59 6.29 2.48 Week 11C-ii 0.1% 96.34 0.02 0.73 0.546.53 2.57 2 11C-i 0.5% 93.76 0.01 1.32 0.59 8.81 5.00 Weeks 11C-ii 0.1%91.41 0.01 1.17 0.51 9.05 5.09

EXAMPLE 11D Dronabinol Solution in Sesame Oil Sourced from Arista—Vials

In Example 11D, dronabinol formulations 11D-i and 11D-ii were preparedin accordance with Examples 11A-i and 11A-ii using sesame oil sourcedfrom Arista. Formulation 11A-i contained 0.5% myristic acid andformulation 11A-ii contained 0.1% myristic acid. The dronabinolformulations were then used to fill amber glass vials. The formulationswithin the vials were initially tested, then tested at 25° C. for 3 and6 months; 40° C. for 1, 2 and 3 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 11D-i-ii at 25° C. are setforth in Table 75 below. TABLE 75 Myristic acid Total Impurities 25° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 11D-i 0.5% 100.000.03 0.52 0.50 3.95 11D-ii 0.1% 100.00 0.02 0.49 0.51 3.91 3 11D-i 0.5%94.69 0.25 0.73 0.48 5.44 1.49 Months 11D-ii 0.1% 92.42 0.32 0.56 0.485.61 1.70 6 11D-i 0.5% 97.08 0.30 1.14 0.50 7.22 3.27 Months 11D-ii 0.1%94.41 0.38 0.82 0.46 8.08 4.17

The results of stability testing of Example 11D-i-ii at 40° C. are setforth in Table 76 below. TABLE 76 D8- Total Impurities Myristic acidPotency CBD CBN THC Increase + 40° C. % % % % % % Zero 11D-i 0.5% 100.000.03 0.52 0.50 3.95 11D-ii 0.1% 100.00 0.02 0.49 0.51 3.91 1 11D-i 0.5%94.98 0.16 0.72 0.53 6.21 2.26 Month 11D-ii 0.1% 93.33 0.16 0.53 0.556.33 2.42 2 11D-i 0.5% 91.54 0.32 1.12 0.47 8.02 4.07 Months 11D-ii 0.1%89.55 0.42 0.75 0.54 9.37 5.46 3 11D-i 0.5% 88.57 0.36 2.00 0.50 12.959.00 Months 11D-ii 0.1% 85.47 0.54 1.35 0.52 14.98 11.07

The results of stability testing of Example 11D-i-ii at 55° C. are setforth in Table 77 below. TABLE 77 D8- Total Impurities Myristic acidPotency CBD CBN THC Increase + 55° C. % % % % % % Zero 11D-i 0.5% 100.000.03 0.52 0.50 3.95 11D-ii 0.1% 100.00 0.02 0.49 0.51 3.91 1 11D-i 0.5%91.53 0.03 1.53 0.59 10.33 6.38 Week 11D-ii 0.1% 87.94 0.01 0.92 0.4913.11 9.20 2 11D-i 0.5% 88.83 0.01 2.10 0.55 12.76 8.81 Weeks 11D-ii0.1% 71.58 0.03 2.16 0.58 23.69 19.78

EXAMPLE 11E Dronabinol Solution in Sesame Oil Sourced from Croda—Vials

In Example 11E, dronabinol formulations 11E-i and 11E-ii were preparedin accordance with Examples 11B-i and 11B-ii using sesame oil sourcedfrom Croda. Formulation 11E-i contained 0.5% myristic acid andformulation 11E-ii contained 0.1% myristic acid. The dronabinolformulations were then used to fill amber glass vials. The formulationswithin the vials were initially tested, then tested at 25° C. for 3 and6 months; 40° C. for 1, 2 and 3 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 11E-i-ii at 25° C. are setforth in Table 78 below. TABLE 78 D8- Total Impurities Myristic acidPotency CBD CBN THC Increase + 25° C. % % % % % % Zero 11E-i 0.5% 100.000.03 0.48 0.65 5.69 11E-ii 0.1% 100.00 0.02 0.46 0.62 2.29 3 11E-i 0.5%80.55 2.17 2.98 0.61 17.38 11.69 Months 11E-ii 0.1% 81.10 3.13 1.26 0.5219.40 14.11 6 11E-i 0.5% 73.95 1.48 6.08 0.78 24.05 18.36 Months 11E-ii0.1% 74.74 3.36 2.78 0.53 24.73 19.44

The results of stability testing of Example 11E-i-ii at 40° C. are setforth in Table 79 below. TABLE 79 D8- Total Impurities Myristic acidPotency CBD CBN THC Increase + 40° C. % % % % % % Zero 11E-i 0.5% 100.000.03 0.48 0.65 5.69 11E-ii 0.1% 100.00 0.02 0.46 0.62 2.29 1 11E-i 0.5%86.99 1.07 2.12 0.59 14.05 8.36 Month 11E-ii 0.1% 75.78 3.06 1.74 0.5624.01 18.72 2 11E-i 0.5% 74.43 1.22 4.09 0.68 20.17 14.48 Months 11E-ii0.1% 61.23 3.47 3.52 0.63 30.90 25.61 3 11E-i 0.5% 66.67 1.13 6.94 0.6928.15 22.46 Months 11E-ii 0.1% 54.34 2.95 5.83 0.74 36.97 31.68

The results of stability testing of Example 11E-i-ii at 55° C. are setforth in Table 80 below. TABLE 80 D8- Total Impurities Myristic acidPotency CBD CBN THC Increase + 55° C. % % % % % % Zero 11E-i 0.5% 100.000.03 0.48 0.65 5.69 11E-ii 0.1% 100.00 0.02 0.46 0.62 2.29 1 11E-i 0.5%87.77 0.01 1.99 0.63 14.67 8.98 Week 11E-ii 0.1% 85.94 0.03 0.96 0.5217.11 11.82 2 11E-i 0.5% 46.26 0.05 10.13 1.16 45.43 39.74 Weeks 11E-ii0.1% 33.85 0.09 5.57 0.65 57.47 52.18

EXAMPLE 11F Dronabinol Solution in Sesame Oil Sourced from Dipasa—Vials

In Example 11F, dronabinol formulations 11F-i and 11F-ii were preparedin accordance with Examples 11C-i and 11C-ii using sesame oil sourcedfrom Dipasa. Formulation 11F-i contained 0.5% myristic acid andformulation 11F-ii contained 0.1% myristic acid. The dronabinolformulations were then used to fill amber glass vials. The formulationswithin the vials were initially tested, then tested at 25° C. for 3 and6 months; 40° C. for 1, 2 and 3 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 11F-i-ii at 25° C. are setforth in Table 81 below. TABLE 81 D8- Total Impurities Myristic acidPotency CBD CBN THC Increase + 25° C. % % % % % % Zero 11F-i 0.5% 100.000.06 0.53 0.54 3.81 11F-ii 0.1% 100.00 0.02 0.56 0.60 3.96 3 11F-i 0.5%92.80 0.21 0.82 0.52 5.56 1.75 Months 11F-ii 0.1% 93.41 0.23 0.74 0.535.55 1.59 6 11F-i 0.5% 95.57 0.29 1.28 0.55 7.66 3.85 Months 11F-ii 0.1%94.87 0.37 1.06 0.58 7.86 3.90

The results of stability testing of Example 11F-i-ii at 40° C. are setforth in Table 82 below. TABLE 82 D8- Total Impurities Myristic acidPotency CBD CBN THC Increase + 40° C. % % % % % % Zero 11F-i 0.5% 100.000.06 0.53 0.54 3.81 11F-ii 0.1% 100.00 0.02 0.56 0.60 3.96 1 11F-i 0.5%94.33 0.14 0.86 0.61 6.78 2.97 Month 11F-ii 0.1% 94.02 0.14 0.74 0.606.34 2.38 2 11F-i 0.5% 89.60 0.26 1.47 0.62 9.75 5.94 Months 11F-ii 0.1%89.94 0.39 1.24 0.64 10.12 6.16 3 11F-i 0.5% 86.61 0.34 2.45 0.55 14.4710.66 Months 11F-ii 0.1% 86.26 0.50 2.01 0.56 15.46 11.50

The results of stability testing of Example 11F-i-ii at 55° C. are setforth in Table 83 below. TABLE 83 D8- Total Impurities Myristic acidPotency CBD CBN THC Increase + 55° C. % % % % % % Zero 11F-i 0.5% 100.000.06 0.53 0.54 3.81 11F-ii 0.1% 100.00 0.02 0.56 0.60 3.96 1 11F-i 0.5%97.34 0.01 0.81 0.59 6.29 2.48 Week 11F-ii 0.1% 96.34 0.02 0.73 0.546.53 2.57 2 11F-i 0.5% 93.76 0.01 1.32 0.59 8.81 5.00 Weeks 11F-ii 0.1%91.41 0.01 1.17 0.51 9.05 5.09

As can be seen from the above results, myristic acid imparts instabilityto dronabinol formulation at all temperature conditions studied.However, dronabinol in sesame oil sourced from Dipasa is resistant todegradation from exposure to myristic acid to some extent. Thisstability can be attributed to the presence of high levels of theantioxidant lecithin in sesame oil sourced from Dipasa.

EXAMPLE 12 Stability Results—Presence of Base(s)

In Example 12, the effect of added bases in dronabinol formulated as asesame oil solution was evaluated. In each of Examples 12-i-12-xiv, thespecified amount of base was added to the formulation prepared inaccordance with Example 1.

Example 12-i is a solution of dronabinol (3.03% w/w) and 2% (w/v)ethanolamine in sesame oil, NF (by Arista).

Example 12-ii is a solution of dronabinol (3.03% w/w) and 1% (w/v)ethanolamine in sesame oil, NF (by Arista).

Example 12-iii is a solution of dronabinol (3.03% w/w) and 0.5% (w/v)ethanolamine in sesame oil, NF (by Arista).

Example 12-iv is a solution of dronabinol (3.03% w/w) and 0.1% (w/v)ethanolamine in sesame oil, NF (by Arista).

Example 12-v is a solution of dronabinol (3.03% w/w) and 0.05% (w/v)ethanolamine in sesame oil, NF (by Arista).

Example 12-vi is a solution of dronabinol (3.03% w/w) and 0.07% (w/v)ethanolamine in sesame oil, NF (by Arista).

Example 12-vii is a solution of dronabinol (3.03% w/w) and 2% (w/v)ethanolamine in sesame oil, super refined NF (by Croda).

Example 12-viii is solution of dronabinol (3.03% w/w) and 1% (w/v)ethanolamine in sesame oil, super refined NF (by Croda).

Example 12-ix is a solution of dronabinol (3.03% w/w) and 0.5% (w/v)ethanolamine in sesame oil, super refined NF (by Croda).

Example 12-x is a solution of dronabinol (3.03% w/w) and 0.1% (w/v)ethanolamine in sesame oil, super refined NF (by Croda).

Example 12-xi is a solution of dronabinol (3.03% w/w) and 0.05% (w/v)ethanolamine in sesame oil, super refined NF (by Croda).

Example 12-xii is a solution of dronabinol (3.03% w/w) and 0.07% (w/v)ethanolamine in sesame oil, super refined NF (by Croda).

Example 12-xiii is a solution of dronabinol (3.03% w/w) and 0.01% (w/v)meglumine in sesame oil, NF (by Arista).

Example 12-xiv is a solution of dronabinol (3.03% w/w) and 0.1% (w/v)ethanolamine in sesame oil, NF (by Arista).

A summary of the compositions of Examples 12i-12iv is set forth in Table84 below: TABLE 84 Composition Formulation No. Dronabinol Sesame OilOther Ingredients Example 12-i 3.03% w/w QS Ethanolamine (2%) Example12-ii 3.03% w/w QS Ethanolamine (1%) Example 12-iii 3.03% w/w QSEthanolamine (0.5%) Example 12-iv 3.03% w/w QS Ethanolamine (0.1%)Example 12-v 3.03% w/w QS Ethanolamine (0.05%) Example 12-vi 3.03% w/wQS Ethanolamine (0.07%) Example 12-vii 3.03% w/w QS Ethanolamine (2%)Example 12-viii 3.03% w/w QS Ethanolamine (1%) Example 12-ix 3.03% w/wQS Ethanolamine (0.5%) Example 12-x 3.03% w/w QS Ethanolamine (0.1%)Example 12-xi 3.03% w/w QS Ethanolamine (0.05%) Example 12-xii 3.03% w/wQS Ethanolamine (0.07%) Example 12-xiii 3.03% w/w QS meglumine (0.01%)Example 12-xiv 3.03% w/w QS Ethanolamine (0.1%)

The formulations were stored in amber glass vials at 55° C. and placedunder accelerated stability conditions at 55° C. The results of thestability study after one week are presented in Table 85 and after twoweeks are presented in Table 86.

Table 85: Stability of Dronabinol Formulations in the Presence of Basesat 55° C., 1 week TABLE 85 RELATED TOTAL SUBSTANCES ASSAY IMPURITY D8THCCBN CBD FORMULATION* # % % % % % Example 12-i 91.97 8.03 0.59 1.30 0.55(A + EA 2%) Example 12-iii 94.58 5.42 0.43 1.21 0.32 (A + EA 0.5%)Example 12-v 93.82 6.18 0.43 1.20 0.15 (A + EA 0.05%) Example 12-xiii95.14 4.86 0.35 0.64 0.49 (A + Meglumine 0.01%) Example 12-xiv 95.014.99 0.56 0.86 0.35 (A + EA 0.1%) Example 12-viii 94.56 5.44 0.45 1.230.48 (C + EA 1%) Example 12-xj 94.65 5.35 0.50 1.22 0.12 (C + EA 0.1%)Example 12-xii 94.09 5.95 0.47 1.24 0.25 (C + EA 0.007%)*A = Arista, C = Croda, EA = Ethanolamine

Table 86: Stability of Dronabinol Formulations in the Presence of Basesat 55° C., 2 weeks TABLE 86 RELATED TOTAL SUBSTANCES ASSAY IMPURITYD8THC CBN CBD FORMULATION* # % % % % % Example 12-i 91.16 8.84 0.51 2.000.67 (A + EA 2%) Example 12-iii 93.88 6.12 0.47 1.57 0.31 (A + EA 0.5%)Example 12-v 92.07 7.93 0.46 1.87 0.10 (A + EA 0.05%) Example 12-xiii92.17 7.83 0.48 1.30 0.42 (A + Meglumine 0.01%) Example 12-xiv 91.638.37 0.56 2.28 0.17 (A + EA 1%) Example 12-viii 93.53 6.47 0.53 1.700.65 (C + EA 1%) Example 12-x 92.68 7.32 0.54 1.51 0.13 (C + EA 0.1%)Example 12-xii 91.49 8.51 0.47 1.78 0.06 (C + EA 0.007%)*A = Arista, C = Croda, EA = Ethanolamine

A significant improvement in the stability of dronabinol formulationswas observed for all the bases (amines) studied.

Extended Stability Results—Addition of Base(s)

To confirm whether the addition of the organic bases monoethanolamine ormeglumine to the dronabinol formulations created more stabileformulations, stability studies at room temperature and at acceleratedconditions over an extended period of time were conducted using sesameoil from Arista, Croda and Dipasa.

EXAMPLE 12A Dronabinol Solution in Sesame Oil Sourced fromArista—Capsules

In Example 12A, dronabinol formulations 12A-i, 12A-ii and 12A-iii wereprepared in accordance with Examples 12-ii, 12-iii and 12-iv,respectively using sesame oil sourced from Arista. Formulation 12A-icontained 1% monoethanolamine, formulation 12A-ii contained 0.5%monoethanolamine and 12A-iii contained 0.01% monoethanolamine. Thedronabinol formulations were then used to fill hard gelatin capsules inaccordance with Example 2. The formulations within the capsules wereinitially tested, then tested at 25° C. for 3 and 6 months; 40° C. for1, 2 and 3 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 12A-i-iii at 25° C. are setforth in Table 87 below. TABLE 87 Monoethanolamine Total Impurities 25°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 12A-i 1% 100.000.02 0.72 0.52 4.90 12A-ii 0.5% 100.00 0.01 0.58 0.49 4.14 12A-iii100.00 0.02 0.50 0.54 3.71 0.01% 3 12A-i 1% 97.48 0.11 0.81 0.51 5.130.23 Months 12A-ii 0.5% 96.11 0.20 0.71 0.47 5.16 1.02 12A-iii 90.670.65 0.67 0.43 10.23 6.52 0.01% 6 12A-i 1% 99.48 0.14 0.93 0.52 5.650.75 Months 12A-ii 0.5% 100.72 0.19 0.85 0.51 5.85 1.71 12A-iii 91.631.04 0.87 0.51 12.50 8.79 0.01%

The results of stability testing of Example 12A-i-iii at 40° C. are setforth in Table 88 below. TABLE 88 Monoethanolamine Total Impurities 40°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 12A-i 1% 100.000.02 0.72 0.52 4.90 12A-ii 0.5% 100.00 0.01 0.58 0.49 4.14 12A-iii100.00 0.02 0.50 0.54 3.71 0.01% 1 12A-i 1% 98.57 0.13 0.70 0.51 5.190.29 Month 12A-ii 0.5% 98.53 0.24 0.75 0.48 5.71 1.57 12A-iii 91.50 0.660.68 0.48 10.49 6.78 0.01% 2 12A-i 1% 96.11 0.08 0.97 0.50 5.23 0.33Months 12A-ii 0.5% 97.47 0.16 1.05 0.49 5.91 1.77 12A-iii 90.79 0.400.78 0.48 10.84 7.13 0.01% 3 12A-i 1% 96.30 0.17 1.39 0.47 4.96 0.06Months 12A-ii 0.5% 94.76 0.24 1.32 0.39 5.75 1.61 12A-iii 89.19 0.660.99 0.44 11.40 7.69 0.01%

The results of stability testing of Example 12A-i-iii at 55° C. are setforth in Table 89 below. TABLE 89 Monoethanolamine Total Impurities 55°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 12A-i 1% 100.000.02 0.72 0.52 4.90 12A-ii 0.5% 100.00 0.01 0.58 0.49 4.14 12A-iii100.00 0.02 0.50 0.54 3.71 0.01% 1 12A-i 1% 98.76 0.01 1.01 0.55 6.611.71 Week 12A-ii 0.5% 96.97 0.01 0.88 0.53 6.15 2.01 12A-iii 97.85 0.020.50 0.51 6.14 2.43 0.01% 2 12A-i 1% 96.66 0.01 1.38 0.52 7.32 2.42Weeks 12A-ii 0.5% 97.17 0.01 1.17 0.53 7.23 3.09 12A-iii 97.56 0.01 0.530.51 7.77 4.06 0.01%

EXAMPLE 12B Dronabinol Solution in Sesame Oil Sourced fromCroda—Capsules

In Example 12B, dronabinol formulations 12B-i, 12B-ii and 12B-iii wereprepared in accordance with Examples 12-viii, 12-ix and 12-x,respectively using sesame oil sourced from Croda. Formulation 12B-icontained 1% monoethanolamine, formulation 12B-ii contained 0.5%monoethanolamine and 12B-iii contained 0.01% monoethanolamine. Thedronabinol formulations were then used to fill hard gelatin capsules inaccordance with Example 2. The formulations within the capsules wereinitially tested, then tested at 25° C. for 3 and 6 months; 40° C. for1, 2 and 3 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 12B-i-iii at 25° C. are setforth in Table 90 below. TABLE 90 Monoethanolamine Total Impurities 25°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 12B-i 1% 100.000.01 0.60 0.53 6.71 12B-ii 0.5% 100.00 0.03 0.55 0.58 5.35 12B-iii100.00 0.01 0.44 0.58 3.99 0.01% 3 12B-i 1% 93.45 0.25 0.78 0.58 6.36−0.35 Months 12B-ii 0.5% 91.37 0.41 0.89 0.53 6.36 1.01 12B-iii 89.100.65 0.55 0.49 12.83 8.84 0.01% 6 12B-i 1% 98.56 0.08 0.93 0.59 6.50−0.21 Months 12B-ii 0.5% 98.51 0.18 1.18 0.57 6.62 1.27 12B-iii 96.840.36 0.75 0.55 6.87 3.07 0.01%

The results of stability testing of Example 12B-i-iii at 40° C. are setforth in Table 91 below. TABLE 91 Monoethanolamine Total Impurities 40°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 12B-i 1% 100.000.01 0.60 0.53 6.71 12B-ii 0.5% 100.00 0.03 0.55 0.58 5.35 12B-iii100.00 0.01 0.44 0.58 3.99 0.01% 1 12B-i 1% 96.77 0.19 0.81 0.57 6.46−0.25 Month 12B-ii 0.5% 96.45 0.36 1.02 0.55 7.24 1.89 12B-iii 90.390.91 0.60 0.56 12.34 8.35 0.01% 2 12B-i 1% 94.28 0.14 1.05 0.54 6.38−0.33 Months 12B-ii 0.5% 93.34 0.15 1.41 0.52 7.40 2.05 12B-iii 87.540.56 0.64 0.54 12.64 8.65 0.01% 3 12B-i 1% 94.00 0.46 1.44 0.52 6.47−0.24 Months 12B-ii 0.5% 93.05 0.30 1.75 0.47 7.69 2.34 12B-iii 85.610.91 0.85 0.54 14.32 10.33 0.01%

The results of stability testing of Example 12B-i-iii at 55° C. are setforth in Table 92 below. TABLE 92 Monoethanolamine Total Impurities 55°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 12B-i 1% 100.000.01 0.60 0.53 6.71 12B-ii 0.5% 100.00 0.03 0.55 0.58 5.35 12B-iii100.00 0.01 0.44 0.58 3.99 0.01% 1 12B-i 1% 96.00 0.01 0.94 0.58 7.791.08 Week 12B-ii 0.5% 97.27 0.07 0.99 0.57 7.30 1.95 12B-iii 91.46 0.030.48 0.54 14.81 10.82 0.01% 2 12B-i 1% 92.98 0.01 1.55 0.60 8.43 1.72Weeks 12B-ii 0.5% 99.09 0.01 1.45 0.58 7.71 2.36 12B-iii 31.14 0.08 2.790.56 63.47 59.48 0.01%

EXAMPLE 12C Dronabinol Solution in Sesame Oil Sourced fromDipasa—Capsules

In Example 12C, dronabinol formulations 12C-i, 12C-ii and 12C-iii wereprepared in accordance with Examples 12B-i-iii respectively using sesameoil sourced from Dipasa. Formulation 12C-i contained 1%monoethanolamine, formulation 12C-ii contained 0.5% monoethanolamine and12C-iii contained 0.01% monoethanolamine. The dronabinol formulationswere then used to fill hard gelatin capsules in accordance with Example2. The formulations within the capsules were initially tested, thentested at 25° C. for 3 and 6 months; 40° C. for 1, 2 and 3 months and at55° C. for 1 and 2 weeks.

The results of stability testing of Example 12C-i-iii at 25° C. are setforth in Table 93 below. TABLE 93 Monoethanolamine Total Impurities 25°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 12C-i 1% 100.000.02 0.72 0.56 5.45 12C-ii 0.5% 100.00 0.02 0.61 0.54 4.31 12C-iii100.00 0.03 0.53 0.58 3.80 0.01% 3 12C-i 1% 94.00 0.22 0.87 0.56 5.44−0.01 Months 12C-ii 0.5% 94.33 0.08 0.84 0.52 5.17 0.86 12C-iii 94.260.18 0.61 0.50 4.88 1.08 0.01% 6 12C-i 1% 97.99 0.16 0.97 0.55 5.99 0.54Months 12C-ii 0.5% 98.95 0.12 1.05 0.53 5.43 1.12 12C-iii 96.84 0.360.75 0.55 6.87 3.07 0.01%

The results of stability testing of Example 12C-i-iii at 40° C. are setforth in Table 94 below. TABLE 94 Monoethanolamine Total Impurities 40°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 12C-i 1% 100.000.02 0.72 0.56 5.45 12C-ii 0.5% 100.00 0.02 0.61 0.54 4.31 12C-iii100.00 0.03 0.53 0.58 3.80 0.01% 1 12C-i 1% 95.73 0.13 0.76 0.51 5.29−0.16 Month 12C-ii 0.5% 96.70 0.16 0.87 0.52 5.38 1.07 12C-iii 95.420.29 0.61 0.54 6.74 2.94 0.01% 2 12C-i 1% 94.07 0.06 0.91 0.57 5.32−0.13 Months 12C-ii 0.5% 94.47 0.10 1.16 0.53 5.55 1.24 12C-iii 91.050.16 0.82 0.55 9.25 5.45 0.01% 3 12C-i 1% 93.60 0.28 1.24 0.47 5.45 0.00Months 12C-ii 0.5% 93.68 0.13 1.47 0.52 6.21 1.90 12C-iii 90.49 0.331.19 0.56 10.39 6.59 0.01%

The results of stability testing of Example 12C-i-iii at 55° C. are setforth in Table 95 below. TABLE 95 Monoethanolamine Total Impurities 55°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 12C-i 1% 100.000.02 0.72 0.56 5.45 12C-ii 0.5% 100.00 0.02 0.61 0.54 4.31 12C-iii100.00 0.03 0.53 0.58 3.80 0.01% 1 12C-i 1% 95.67 0.01 0.95 0.55 6.861.41 Week 12C-ii 0.5% 97.38 0.05 0.93 0.55 6.03 1.72 12C-iii 97.08 0.010.56 0.54 6.57 2.77 0.01% 2 12C-i 1% 94.76 0.01 0.51 0.52 6.85 1.40Weeks 12C-ii 0.5% 97.43 0.02 1.35 0.54 6.96 2.65 12C-iii 97.56 0.01 0.730.54 8.48 4.68 0.01%

EXAMPLE 12D Dronabinol Solution in Sesame Oil Sourced from Arista—Vials

In Example 12D, dronabinol formulations 12D-i, 12D-ii and 12D-iii wereprepared in accordance with Examples 12A-i, 12A-ii and 12A-iii,respectively using sesame oil sourced from Arista. Formulation 12A-icontained 1% monoethanolamine, formulation 12A-ii contained 0.5%monoethanolamine and 12A-iii contained 0.01% monoethanolamine. Thedronabinol formulations were then used to fill amber glass vials. Theformulations within the vials were initially tested, then tested at 25°C. for 3 and 6 months; 40° C. for 1, 2 and 3 months and at 55° C. for 1and 2 weeks.

The results of stability testing of Example 12D-i-iii at 25° C. are setforth in Table 96 below. TABLE 96 Monoethanolamine Total Impurities 25°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 12D-i 1% 100.000.02 0.72 0.52 4.90 12D-ii 0.5% 100.00 0.01 0.58 0.49 4.14 12D-iii100.00 0.02 0.50 0.54 3.71 0.01% 3 12D-i 1% 95.09 0.10 1.07 0.50 5.981.08 Months 12D-ii 0.5% 95.26 0.34 0.86 0.48 5.53 1.39 12D-iii 95.340.12 0.52 0.48 4.83 1.12 0.01% 6 12D-i 1% 99.49 0.06 1.48 0.51 6.62 1.72Months 12D-ii 0.5% 99.30 0.13 1.09 0.52 6.23 2.09 12D-iii 98.65 0.160.59 0.48 6.22 2.51 0.01%

The results of stability testing of Example 12D-i-iii at 40° C. are setforth in Table 97 below. TABLE 97 Monoethanolamine Total Impurities 40°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 12D-i 1% 100.000.02 0.72 0.52 4.90 12D-ii 0.5% 100.00 0.01 0.58 0.49 4.14 12D-iii100.00 0.02 0.50 0.54 3.71 0.01% 1 12D-i 1% 95.67 0.16 1.11 0.56 6.131.23 Month 12D-ii 0.5% 97.85 0.17 0.82 0.54 5.55 1.41 12D-iii 95.46 0.080.46 0.54 5.62 1.91 0.01% 2 12D-i 1% 93.49 0.09 1.31 0.58 6.21 1.31Months 12D-ii 0.5% 93.65 0.16 1.04 0.54 6.30 2.16 12D-iii 93.46 0.170.53 0.55 7.51 3.80 0.01% 3 12D-i 1% 93.40 0.48 2.03 0.45 7.92 3.02Months 12D-ii 0.5% 92.64 0.15 1.70 0.50 8.23 4.09 12D-iii 91.13 0.270.76 0.47 10.43 6.72 0.01%

The results of stability testing of Example 12D-i-iii at 55° C. are setforth in Table 98 below. TABLE 98 Monoethanolamine Total Impurities 55°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 12D-i 1% 100.000.02 0.72 0.52 4.90 12D-ii 0.5% 100.00 0.01 0.58 0.49 4.14 12D-iii100.00 0.02 0.50 0.54 3.71 0.01% 1 12D-i 1% 98.76 0.01 1.01 0.55 6.611.71 Week 12D-ii 0.5% 96.97 0.01 0.88 0.53 6.15 2.01 12D-iii 97.85 0.020.50 0.51 6.14 2.43 0.01% 2 12D-i 1% 96.66 0.01 1.38 0.52 7.32 2.42Weeks 12D-ii 0.5% 97.17 0.01 1.17 0.53 7.23 3.09 12D-iii 97.56 0.01 0.530.51 7.77 4.06 0.01%

EXAMPLE 12E Dronabinol Solution in Sesame Oil Sourced from Croda—Vials

In Example 12E, dronabinol formulations 12E-i, 12E-ii and 12E-iii wereprepared in accordance with Examples 12B-i, 12B-ii and 12B-iii,respectively using sesame oil sourced from Croda. Formulation 12E-icontained 1% monoethanolamine, formulation 12E-ii contained 0.5%monoethanolamine and 12E-iii contained 0.01% monoethanolamine. Thedronabinol formulations were then used to fill amber glass vials. Theformulations within the vials were initially tested, then tested at 25°C. for 3 and 6 months; 40° C. for 1, 2 and 3 months and at 55° C. for 1and 2 weeks.

The results of stability testing of Example 12E-i-iii at 25° C. are setforth in Table 99 below. TABLE 99 Monoethanolamine Total Impurities 25°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 12E-i 1% 100.000.01 0.60 0.53 6.71 12E-ii 0.5% 100.00 0.03 0.55 0.58 5.35 12E-iii100.00 0.01 0.44 0.58 3.99 0.01% 3 12E-i 1% 93.38 0.08 1.02 0.54 6.940.23 Months 12E-ii 0.5% 94.64 0.27 0.94 0.54 6.26 0.91 12E-iii 95.250.14 0.48 0.52 5.30 1.31 0.01% 6 12E-i 1% 97.78 0.03 1.40 0.57 7.43 0.72Months 12E-ii 0.5% 99.21 0.05 1.27 0.56 6.67 1.32 12E-iii 97.81 0.160.51 0.54 6.97 2.98 0.01%

The results of stability testing of Example 12E-i-iii at 40° C. are setforth in Table 100 below. TABLE 100 Monoethanolamine Total Impurities40° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 12E-i 1%100.00 0.01 0.60 0.53 6.71 12E-ii 0.5% 100.00 0.03 0.55 0.58 5.3512E-iii 100.00 0.01 0.44 0.58 3.99 0.01% 1 12E-i 1% 95.45 0.16 1.37 0.627.12 0.41 Month 12E-ii 0.5% 98.70 0.09 0.87 0.61 5.74 0.39 12E-iii 85.860.57 0.54 0.58 16.05 12.06 0.01% 2 12E-i 1% 93.25 0.11 1.26 0.58 7.520.81 Months 12E-ii 0.5% 91.93 0.17 1.21 0.71 7.90 2.55 12E-iii 70.931.27 0.93 0.54 26.35 22.36 0.01% 3 12E-i 1% 92.64 0.49 2.11 0.56 8.802.09 Months 12E-ii 0.5% 93.61 0.06 1.73 0.52 7.28 1.93 12E-iii 61.881.48 1.66 0.57 34.77 30.78 0.01%

The results of stability testing of Example 12E-i-iii at 55° C. are setforth in Table 101 below. TABLE 101 Monoethanolamine Total Impurities55° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 12E-i 1%100.00 0.01 0.60 0.53 6.71 12E-ii 0.5% 100.00 0.03 0.55 0.58 5.3512E-iii 100.00 0.01 0.44 0.58 3.99 0.01% 1 12E-i 1% 96.00 0.01 0.94 0.587.79 1.08 Week 12E-ii 0.5% 97.27 0.07 0.99 0.57 7.30 1.95 12E-iii 91.460.03 0.48 0.54 14.81 10.82 0.01% 2 12E-i 1% 92.98 0.01 1.55 0.60 8.431.72 Weeks 12E-ii 0.5% 99.09 0.01 1.45 0.58 7.71 2.36 12E-iii 31.14 0.082.79 0.56 63.47 59.48 0.01%

EXAMPLE 12F Dronabinol Solution in Sesame Oil Sourced from Dipasa—Vials

In Example 12F, dronabinol formulations 12F-i, 12F-ii and 12F-iii wereprepared in accordance with Examples 12C-i, 12C-ii and 12C-iiirespectively using sesame oil sourced from Dipasa. Formulation 12F-icontained 1% monoethanolamine, formulation 12F-ii contained 0.5%monoethanolamine and 12F-iii contained 0.01% monoethanolamine. Thedronabinol formulations were then used to fill amber glass vials. Theformulations within the glass vials were initially tested, then testedat 25° C. for 3 and 6 months; 40° C. for 1, 2 and 3 months and at 55° C.for 1 and 2 weeks.

The results of stability testing of Example 12F-i-iii at 25° C. are setforth in Table 102 below. TABLE 102 Monoethanolamine Total Impurities25° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 12F-i 1%100.00 0.02 0.72 0.56 5.45 12F-ii 0.5% 100.00 0.02 0.61 0.54 4.3112F-iii 0.01% 100.00 0.03 0.53 0.58 3.80 3 12F-i 1% 93.57 0.15 0.96 0.525.96 0.51 Months 12F-ii 0.5% 93.74 0.12 0.85 0.51 5.33 1.02 12F-iii0.01% 93.39 0.15 0.61 0.52 5.10 1.30 6 12F-i 1% 100.19 0.08 1.28 0.556.55 1.10 Months 12F-ii 0.5% 98.39 0.08 1.12 0.54 5.87 1.56 12F-iii0.01% 97.06 0.19 0.74 0.52 7.25 3.45

The results of stability testing of Example 12F-i-iii at 40° C. are setforth in Table 103 below. TABLE 103 Monoethanolamine Total Impurities40° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 12F-i 1%100.00 0.02 0.72 0.56 5.45 12F-ii 0.5% 100.00 0.02 0.61 0.54 4.3112F-iii 0.01% 100.00 0.03 0.53 0.58 3.80 1 12F-i 1% 94.59 0.22 1.33 0.616.92 1.47 Month 12F-ii 0.5% 93.58 0.19 0.82 0.30 5.05 0.74 12F-iii 0.01%96.17 0.13 0.54 0.60 6.25 2.45 2 12F-i 1% 93.13 0.08 1.26 0.58 6.92 1.47Months 12F-ii 0.5% 91.69 0.09 1.12 0.63 5.94 1.63 12F-iii 0.01% 92.280.24 0.73 0.58 8.15 4.35 3 12F-i 1% 91.51 0.47 2.02 0.55 9.15 3.70Months 12F-ii 0.5% 92.52 0.09 1.72 0.50 7.25 2.94 12F-iii 0.01% 89.340.41 1.15 0.52 12.31 8.51

The results of stability testing of Example 12F-i-iii at 55° C. are setforth in Table 104 below. TABLE 104 Monoethanolamine Total Impurities55° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 12F-i 1%100.00 0.02 0.72 0.56 5.45 12F-ii 0.5% 100.00 0.02 0.61 0.54 4.3112F-iii 0.01% 100.00 0.03 0.53 0.58 3.80 1 12F-i 1% 95.67 0.01 0.95 0.556.86 1.41 Week 12F-ii 0.5% 97.38 0.05 0.93 0.55 6.03 1.72 12F-iii 0.01%97.08 0.01 0.56 0.54 6.57 2.77 2 12F-i 1% 94.76 0.01 0.51 0.52 6.85 1.40Weeks 12F-ii 0.5% 97.43 0.02 1.35 0.54 6.96 2.65 12F-iii 0.01% 97.560.01 0.73 0.54 8.48 4.68

EXAMPLE 12G Dronabinol Solution in Sesame Oil Sourced fromArista—Capsules

In Example 12G, a dronabinol formulation was prepared in accordance withExamples 12-xiii using sesame oil sourced from Arista, containing 0.1%meglumine. The dronabinol formulation was then used to fill hard gelatincapsules in accordance with Example 2. The formulation within thecapsules was initially tested, then tested at 25° C. for 3 and 6 months;40° C. for 1, 2 and 3 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 12G at 25° C. are set forthin Table 105 below. TABLE 105 Meglumine Total Impurities 25° C. Potency% CBD % CBN % D8-THC % % Increase + % Zero 0.1% 100.00 0.05 0.50 0.544.78 3 Months 0.1% 90.70 0.40 0.57 0.48 9.57 4.79 6 Months 0.1% 92.350.65 0.64 0.51 11.19 6.41

The results of stability testing of Example 12G at 40° C. are set forthin Table 106 below. TABLE 106 Meglumine Total Impurities 40° C. Potency% CBD % CBN % D8-THC % % Increase + % Zero 0.1% 100.00 0.05 0.50 0.544.78 1 Month 0.1% 92.30 0.50 0.55 0.47 9.21 4.43 2 Months 0.1% 89.120.40 0.65 0.52 10.84 6.06 3 Months 0.1% 87.11 0.78 0.87 0.45 11.67 6.89

The results of stability testing of Example 12G at 55° C. are set forthin Table 107 below. TABLE 107 Total Impurities Meglumine Potency CBD CBND8-THC Increase + 55° C. % % % % % % Zero 0.1% 100.00 0.05 0.50 0.544.78 1 Week 0.1% 98.13 0.02 0.48 0.52 4.71 −0.07 2 Weeks 0.1% 96.55 0.010.47 0.54 6.27 1.49

EXAMPLE 12H Dronabinol Solution in Sesame Oil Sourced fromCroda—Capsules

In Example 12H, a dronabinol formulation was prepared in accordance withExamples 12G using sesame oil sourced from Croda, containing 0.1%meglumine. The dronabinol formulation was then used to fill hard gelatincapsules in accordance with Example 2. The formulation within thecapsules was initially tested, then tested at 25° C. for 3 and 6 months;40° C. for 1, 2 and 3 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 12H at 25° C. are set forthin Table 108 below. TABLE 108 Total Impurities Meglumine Potency CBD CBND8-THC Increase + 25° C. % % % % % % Zero 0.1% 100.00 0.06 0.43 0.584.11 3 Months 0.1% 88.79 0.68 0.51 0.53 11.38 7.27 6 Months 0.1% 88.490.93 0.67 0.56 14.27 10.16

The results of stability testing of Example 12H at 40° C. are set forthin Table 109 below. TABLE 109 Total Impurities Meglumine Potency CBD CBND8-THC Increase + 40° C. % % % % % % Zero 0.1% 100.00 0.06 0.43 0.584.11 1 Month 0.1% 89.79 0.74 0.46 0.52 11.09 6.98 2 Months 0.1% 85.700.60 0.47 0.52 12.16 8.05 3 Months 0.1% 84.98 0.97 0.63 0.52 14.10 9.99

The results of stability testing of Example 12H at 55° C. are set forthin Table 110 below. TABLE 110 Total Impurities Meglumine Potency CBD CBND8-THC Increase + 55° C. % % % % % % Zero 0.1% 100.00 0.06 0.43 0.584.11 1 Week 0.1% 86.96 0.03 0.55 0.53 14.35 10.24 2 Weeks 0.1% 23.630.11 2.35 0.62 68.45 64.34

EXAMPLE 12I Dronabinol Solution in Sesame Oil Sourced fromDipasa—Capsules

In Example 12I, a dronabinol formulation was prepared in accordance withExample 12G using sesame oil sourced from Dipasa, containing 0.1%meglumine. The dronabinol formulation was then used to fill hard gelatincapsules in accordance with Example 2. The formulation within thecapsules was initially tested, then tested at 25° C. for 3 and 6 months;40° C. for 1, 2 and 3 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 12I at 25° C. are set forthin Table 111 below. TABLE 111 Total Impurities Meglumine Potency CBD CBND8-THC Increase + 25° C. % % % % % % Zero 0.1% 100.00 0.01 0.51 0.543.84 3 Months 0.1% 94.91 0.08 0.55 0.52 5.19 1.35 6 Months 0.1% 99.210.17 0.61 0.55 6.67 2.83

The results of stability testing of Example 12I at 40° C. are set forthin Table 112 below. TABLE 112 Total Impurities Meglumine Potency CBD CBND8-THC Increase + 40° C. % % % % % % Zero 0.1% 100.00 0.01 0.51 0.543.84 1 Month 0.1% 93.78 0.21 0.61 0.53 7.31 3.47 2 Months 0.1% 91.710.11 0.75 0.54 9.13 5.29 3 Months 0.1% 88.91 0.31 1.05 0.54 10.44 6.60

The results of stability testing of Example 12I at 55° C. are set forthin Table 113 below. TABLE 113 Total Impurities Meglumine Potency CBD CBND8-THC Increase + 55° C. % % % % % % Zero 0.1% 100.00 0.01 0.51 0.543.84 1 Week 0.1% 96.96 0.02 0.52 0.56 5.00 1.16 2 Weeks 0.1% 94.25 0.010.56 0.54 6.96 3.12

EXAMPLE 12J Dronabinol Solution in Sesame Oil Sourced from Arista—Vials

In Example 12J, a dronabinol formulation was prepared in accordance withExample 12G using sesame oil sourced from Arista, containing 0.1%meglumine. The dronabinol formulation was then used to fill amber glassvials. The formulation within the vials was initially tested, thentested at 25° C. for 3 and 6 months; 40° C. for 1, 2 and 3 months and at55° C. for 1 and 2 weeks.

The results of stability testing of Example 12J at 25° C. are set forthin Table 114 below. TABLE 114 Total Impurities Meglumine Potency CBD CBND8-THC Increase + 25° C. % % % % % % Zero 0.1% 100.00 0.05 0.50 0.544.78 3 Months 0.1% 94.70 0.06 0.51 0.50 4.64 −0.14 6 Months 0.1% 97.710.09 0.53 0.49 6.01 1.23

The results of stability testing of Example 12J at 40° C. are set forthin Table 115 below. TABLE 115 Total Impurities Meglumine Potency CBD CBND8-THC Increase + 40° C. % % % % % % Zero 0.1% 100.00 0.05 0.50 0.544.78 1 Month 0.1% 96.40 0.01 0.45 0.55 4.67 0.11 2 Months 0.1% 92.860.10 0.46 0.57 6.66 1.88 3 Months 0.1% 92.70 0.10 0.59 0.50 8.68 3.90

The results of stability testing of Example 12J at 55° C. are set forthin Table 116 below. TABLE 116 Total Impurities Meglumine Potency CBD CBND8-THC Increase + 55° C. % % % % % % Zero 0.1% 100.00 0.05 0.50 0.544.78 1 Week 0.1% 98.13 0.02 0.48 0.52 4.71 −0.07 2 Weeks 0.1% 96.55 0.010.47 0.54 6.27 1.49

EXAMPLE 12K Dronabinol Solution in Sesame Oil Sourced from Croda—Vials

In Example 12K, a dronabinol formulation was prepared in accordance withExample 12G using sesame oil sourced from Croda, containing 0.1%meglumine. The dronabinol formulation was then used to fill amber glassvials. The formulation within the vials was initially tested, thentested at 25° C. for 3 and 6 months; 40° C. for 1, 2 and 3 months and at55° C. for 1 and 2 weeks.

The results of stability testing of Example 12K at 25° C. are set forthin Table 117 below. TABLE 117 Total Impurities Meglumine Potency CBD CBND8-THC Increase + 25° C. % % % % % % Zero 0.1% 100.00 0.06 0.43 0.584.11 3 Months 0.1% 93.99 0.27 0.46 0.55 5.67 1.56 6 Months 0.1% 96.450.12 0.47 0.54 6.99 2.88

The results of stability testing of Example 12K at 40° C. are set forthin Table 118 below. TABLE 118 Total Impurities Meglumine Potency CBD CBND8-THC Increase + 40° C. % % % % % % Zero 0.1% 100.00 0.06 0.43 0.584.11 1 Month 0.1% 88.41 0.38 0.46 0.58 11.89 7.78 2 Months 0.1% 78.100.57 0.54 0.64 18.28 14.17 3 Months 0.1% 74.65 0.48 0.82 0.57 21.7517.64

The results of stability testing of Example 12K at 55° C. are set forthin Table 119 below. TABLE 119 Total Impurities Meglumine Potency CBD CBND8-THC Increase + 55° C. % % % % % % Zero 0.1% 100.00 0.06 0.43 0.584.11 1 Week 0.1% 86.96 0.03 0.55 0.53 14.35 10.24 2 Weeks 0.1% 23.630.11 2.35 0.62 68.45 64.34

EXAMPLE 12L Dronabinol Solution in Sesame Oil Sourced from Dipasa—Vials

In Example 12L, a dronabinol formulation was prepared in accordance withExample 12G using sesame oil sourced from Dipasa, containing 0.1%meglumine. The dronabinol formulation was then used to fill amber glassvials. The formulation within the vials was initially tested, thentested at 25° C. for 3 and 6 months; 40° C. for 1, 2 and 3 months and at55° C. for 1 and 2 weeks.

The results of stability testing of Example 12L at 25° C. are set forthin Table 120 below. TABLE 120 Total Impurities Meglumine Potency CBD CBND8-THC Increase + 25° C. % % % % % % Zero 0.1% 100.00 0.01 0.51 0.543.84 3 Months 0.1% 94.31 0.06 0.55 0.54 4.67 0.83 6 Months 0.1% 97.440.10 0.57 0.54 6.19 2.35

The results of stability testing of Example 12L at 40° C. are set forthin Table 121 below. TABLE 121 Total Impurities Meglumine Potency CBD CBND8-THC Increase + 40° C. % % % % % % Zero 0.1% 100.00 0.01 0.51 0.543.84 1 Month 0.1% 93.37 0.05 0.48 0.59 5.54 1.70 2 Months 0.1% 91.710.04 0.55 0.60 6.90 3.06 3 Months 0.1% 90.02 0.10 0.78 0.54 9.03 5.19

The results of stability testing of Example 12L at 55° C. are set forthin Table 122 below. TABLE 122 Total Impurities Meglumine Potency CBD CBND8-THC Increase + 55° C. % % % % % % Zero 0.1% 100.00 0.01 0.51 0.543.84 1 Week 0.1% 96.96 0.02 0.52 0.56 5.00 1.16 2 Weeks 0.1% 94.25 0.010.56 0.54 6.96 3.12

As can be seen from the above results, the addition of organic basesmonoethanolamine or meglumine imparts stability to dronabinolformulations particularly at the higher concentrations. However,monoethanolamine is superior to meglumine in stabilizing dronabinolformulations at all conditions studied.

EXAMPLE 13 Stability Results—Presence of Anti-Oxidants

As previously mentioned, the antioxidant effect of sesame oil has beenattributed to the presence of several antioxidant chemicals in sesameoil, including sesamin, sesamol, sesamolin and lecithin. In Example 13,the effect of added anti-oxidant in hard gelatin capsules of Dronabinolformulated as a sesame oil solution was evaluated. In each of Examples13a-13l, the specified amount of anti-oxidant was added to theformulation prepared in accordance with Examples 1 and 2 (except forExample 13j, which was not encapsulated). Well-known anti-oxidants(Featured Excipient: Antioxidants, 1999) d-α-tocopherol, butyl hydroxylanisole (BHA), butyl hydroxyl toluene (BHT), L-ascorbicacid-6-palmitate, lecithin and propyl gallate were added to Dronabinolsesame oil formulation.

Example 13-i is a 5 mg capsule of dronabinol (3.03% w/w) and 0.001%tocopherol (w/w) in sesame oil, super refined NF (by Croda).

Example 13-ii is a 5 mg capsule of dronabinol (3.03% w/w) and 0.05%(w/w) tocopherol in sesame oil, super refined NF (by Croda).

Example 13-iii is a 5 mg capsule of dronabinol (3.03% w/w) and 0.001%butyl hydroxy anisole (BHA) (w/w) in sesame oil, super refined NF (byCroda).

Example 13-iv is a 5 mg capsule of dronabinol (3.03% w/w) and 0.01%butyl hydroxyl anisole (w/w) in sesame oil, super refined NF (by Croda).

Example 13-v is a 5 mg capsule of dronabinol (3.03% w/w) and 0.001%butyl hydroxyl toluene (w/w) in sesame oil, super refined NF (by Croda).

Example 13-vi is a 5 mg capsule of dronabinol (3.03%) and 0.01% butylhydroxyl toluene in sesame oil, super refined NF (by Croda).

Example 13-vii is a 5 mg capsule of dronabinol (3.03% w/w) and 0.01%L-ascorbic acid-6-palmitate (w/w) in sesame oil, super refined NF (byCroda).

Example 13-viii is a 5 mg capsule of dronabinol (3.03% w/w) and 0.1%L-ascorbic acid-6-palmitate (w/w) in sesame oil, super refined NF (byCroda).

Example 13-ix is a 5 mg capsule of dronabinol (3.03% w/w) and 0.3%lecithin (w/w) in sesame oil, super refined NF (by Croda).

Example 13-x is a solution of dronabinol (3.03% w/w) and 8.25% lecithin(w/w) in sesame oil, super refined NF (by Croda).

Example 13-xi is a 5 mg capsule of dronabinol (3.03% w/w) and 0.001%propyl gallate (w/v) in sesame oil, super refined NF (by Croda).

Example 13-xii is a 5 mg capsule of dronabinol (3.03% w/w) and 0.15%propyl gallate (w/v) in sesame oil, super refmned NF (by Croda).

A summary of the compositions of Examples 13-i-13-xii is set forth inTable 123 below: TABLE 123 Composition Formulation Sesame No. DronabinolOil Other Ingredients Example 13-i 5 mg/capsule (3.03%) QS Tocopherol(0.001%) Example 13-ii 5 mg/capsule (3.03%) QS Tocopherol (0.05%)Example 13-iii 5 mg/capsule (3.03%) QS BHA (0.001%) Example 13-iv 5mg/capsule (3.03%) QS BHA (0.01%) Example 13-v 5 mg/capsule (3.03%) QSBHT (0.001%) Example 13-vi 5 mg/capsule (3.03%) QS BHT (0.01%) Example13-vii 5 mg/capsule (3.03%) QS L-ascorbic acid-6- palmitate (0.01%)Example 13-viii 5 mg/capsule (3.03%) QS L-ascorbic acid-6- palmitate(0.1%) Example 13-ix 5 mg/capsule (3.03%) QS Lecithin (0.3%) Example13-x 5 mg/capsule (3.03%) QS Lecithin (8.25%) Example 13-xi 5 mg/capsule(3.03%) QS Propyl Gallate (0.001%) Example 13-xii 5 mg/capsule (3.03%)QS Propyl Gallate (0.15%)

The dronabinol formulations of Examples 13-i-13-xii containinganti-oxidants as set forth above were placed under accelerated stabilitytesting at 55° C. for two weeks. The results of the study are presentedin Table 124 (including a comparison to the results of Example 9ii (noanti-oxidant included TABLE 124 TOTAL RELATED SUBSTANCES CONDITIONFORMULATION # ASSAY % IMPURITY % D8THC % CBN % CBD % Zero Time Example9-ii* 93.80 6.20 0.75 1.88 0.29 (no anti-oxidant added) 55° C. Example9-ii* 67.41 32.59 1.06 4.96 0.29 (2 weeks) (no anti-oxidant added)Example 13-i: A07 92.40 13.18 0.75 2.13 1.05 Tocopherol (0.001%) Example13-ii: A08 86.72 14.46 0.86 2.34 1.40 Tocopherol (0.05%) Example 13-iii:A09 82.68 12.63 0.78 2.11 1.04 BHA (0.001%) Example 13-iv: A10 92.2713.37 0.99 1.98 1.27 BHA (0.01%) Example 13-v: A11 88.54 13.58 0.82 2.131.11 BHT (0.001%) Example 13-vi: A12 90.66 13.40 0.89 2.15 1.10 BHT(0.01%) Example 13-vii: A13 87.57 11.74 0.84 2.23 0.83 L-ascorbicacid-6- palmitate (0.01%) Example 13-viii: A14 93.04 8.95 0.94 2.30 0.52L-ascorbic acid-6- palmitate (0.1%) Example 13-ix: A15 92.19 12.08 0.892.45 0.72 Lecithin (0.3%) Example 13-x: A16 94.24 9.69 0.90 3.22 0.17Lecithin (8.25%) Example 13-xi: A17 90.39 13.11 0.88 2.16 0.98 PropylGallate (0.001%) Example 13-xii: A18 88.66 16.98 0.86 3.59 1.10 PropylGallate (0.15%)*Control

The results indicated that the addition of Lecithin and L-ascorbicacid-6-palmitate to these dronabinol formulations helps stabilize theactive ingredient dronabinol.

Extended Stability Results—Presence of Anti-Oxidants

To further investigate whether the addition of the anti-oxidantslecithin and L-ascorbic acid-6-palmitate to the dronabinol formulationscreated more stabile formulations, stability studies at room temperatureand at accelerated conditions over an extended period of time wereconducted using sesame oil from Arista, Croda and Dipasa.

EXAMPLE 13A Dronabinol Solution in Sesame Oil Sourced fromArista—Capsules

In Example 13A, dronabinol formulations 13A-i, and 13A-ii were preparedin accordance with Examples 13-x and 13-ix, respectively using sesameoil sourced from Arista. Formulation 13A-i contained 8.25% lecithin andformulation 13A-ii contained 0.3% lecithin. The dronabinol formulationswere then used to fill hard gelatin capsules in accordance with Example2. The formulations within the capsules were initially tested, thentested at 25° C. for 3 and 6 months; 40° C. for 1, 2 and 3 months and at55° C. for 1 and 2 weeks.

The results of stability testing of Example 13A-i-ii at 25° C. are setforth in Table 125 below. TABLE 125 Lecithin Total Impurities 25° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 13A-i 8.25% 100.000.04 0.52 0.55 4.03 13A-ii 0.3% 100.00 0.01 0.49 0.53 3.67 3 Months13A-i 8.25% 97.03 0.04 0.61 0.50 4.23 0.20 13A-ii 0.3% 96.94 0.05 0.680.50 4.81 1.14 6 Months 13A-i 8.25% 100.47 0.04 0.72 0.53 5.56 1.5313A-ii 0.3% 100.23 0.08 0.73 0.43 5.51 1.84

The results of stability testing of Example 13A-i-ii at 40° C. are setforth in Table 126 below. TABLE 126 Lecithin Total Impurities 40° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 13A-i 8.25% 100.000.04 0.52 0.55 4.03 13A-ii 0.3% 100.00 0.01 0.49 0.53 3.67 1 Month 13A-i8.25% 101.18 0.01 0.70 0.50 5.16 1.13 13A-ii 0.3% 94.92 0.06 0.88 0.507.72 4.05 2 Months 13A-i 8.25% 96.72 0.04 0.93 0.55 6.13 2.10 13A-ii0.3% 92.12 0.01 1.06 0.53 8.11 4.44 3 Months 13A-i 8.25% 93.30 0.02 1.360.47 7.00 2.97 13A-ii 0.3% 93.24 0.07 1.25 0.52 8.79 5.12

The results of stability testing of Example 13A-i-ii at 55° C. are setforth in Table 127 below. TABLE 127 Lecithin Total Impurities 55° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 13A-i 8.25% 100.000.04 0.52 0.55 4.03 13A-ii 0.3% 100.00 0.01 0.49 0.53 3.67 1 Week 13A-i8.25% 98.88 0.01 0.92 0.51 5.13 1.10 13A-ii 0.3% 99.26 0.02 0.96 0.525.56 1.89 2 Weeks 13A-i 8.25% 96.89 0.01 1.29 0.51 6.17 2.14 13A-ii 0.3%95.62 0.02 1.31 0.50 6.87 3.20

EXAMPLE 13B Dronabinol Solution in Sesame Oil Sourced fromCroda—Capsules

In Example 13B, dronabinol formulations 13B-i, and 13B-ii were preparedin accordance with Examples 13-x and 13-ix, respectively using sesameoil sourced from Croda. Formulation 13B-i contained 8.25% lecithin andformulation 13B-ii contained 0.3% lecithin. The dronabinol formulationswere then used to fill hard gelatin capsules in accordance with Example2. The formulations within the capsules were initially tested, thentested at 25° C. for 3 and 6 months; 40° C. for 1, 2 and 3 months and at55° C. for 1 and 2 weeks.

The results of stability testing of Example 13B-i-ii at 25° C. are setforth in Table 128 below. TABLE 128 Lecithin Total Impurities 25° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 13B-i 8.25% 100.000.02 0.45 0.58 3.73 13B-ii 0.3% 100.00 0.04 0.42 0.56 3.67 3 13B-i 8.25%96.19 0.04 0.69 0.57 4.97 1.24 Months 13B-ii 0.3% 96.70 0.08 0.57 0.544.87 1.20 6 13B-i 8.25% 97.98 0.06 0.76 0.59 6.65 2.92 Months 13B-ii0.3% 98.09 0.15 0.77 0.57 7.14 3.47

The results of stability testing of Example 13B-i-ii at 40° C. are setforth in Table 129 below. TABLE 129 Lecithin Total Impurities 40° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 13B-i 8.25% 100.000.02 0.45 0.58 3.73 13B-ii 0.3% 100.00 0.04 0.42 0.56 3.67 1 13B-i 8.25%94.23 0.02 0.95 0.57 7.43 3.70 Month 13B-ii 0.3% 91.53 0.06 1.16 0.5510.47 6.80 2 13B-i 8.25% 89.93 0.02 1.27 0.65 9.61 5.88 Months 13B-ii0.3% 89.31 0.05 1.43 0.61 12.44 8.77 3 13B-i 8.25% 87.62 0.02 2.01 0.5611.07 7.34 Months 13B-ii 0.3% 86.29 0.10 2.07 0.59 13.25 9.58

The results of stability testing of Example 13B-i-ii at 55° C. are setforth in Table 130 below. TABLE 130 Lecithin Total Impurities 55° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 13B-i 8.25% 100.000.02 0.45 0.58 3.73 13B-ii 0.3% 100.00 0.04 0.42 0.56 3.67 1 13B-i 8.25%97.01 0.03 1.25 0.58 6.43 2.70 Week 13B-ii 0.3% 88.98 0.13 2.51 0.5812.47 8.80 2 13B-i 8.25% 92.29 0.02 1.89 0.53 8.50 4.77 Weeks 13B-ii0.3% 43.06 0.16 10.13 1.19 49.26 45.59

EXAMPLE 13C Dronabinol Solution in Sesame Oil Sourced fromDipasa—Capsules

In Example 13C, dronabinol formulations 13C-i, and 13C-ii were preparedin accordance with Examples 13-x and 13-ix, respectively using sesameoil sourced from Dipasa. Formulation 13C-i contained 8.25% lecithin andformulation 13C-ii contained 0.3% lecithin. The dronabinol formulationswere then used to fill hard gelatin capsules in accordance with Example2. The formulations within the capsules were initially tested, thentested at 25° C. for 3 and 6 months; 40° C. for 1, 2 and 3 months and at55° C. for 1 and 2 weeks.

The results of stability testing of Example 13C-i-ii at 25° C. are setforth in Table 131 below. TABLE 131 Lecithin Total Impurities 25° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 13C-i 8.25% 100.000.02 0.55 0.59 3.93 13C-ii 0.3% 100.00 0.03 0.53 0.59 3.93 3 13C-i 8.25%96.33 0.05 0.71 0.55 4.84 0.91 Months 13C-ii 0.3% 96.85 0.03 0.81 0.565.17 1.24 6 13C-i 8.25% 98.70 0.04 0.97 0.50 5.56 1.63 Months 13C-ii0.3% 98.81 0.10 0.95 0.50 6.30 2.37

The results of stability testing of Example 13C-i-ii at 40° C. are setforth in Table 132 below. TABLE 132 Lecithin Total Impurities 40° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 13C-i 8.25% 100.000.02 0.55 0.59 3.93 13C-ii 0.3% 100.00 0.03 0.53 0.59 3.93 1 13C-i 8.25%96.94 0.04 0.94 0.55 6.05 2.12 Month 13C-ii 0.3% 96.81 0.06 0.84 0.526.96 3.03 2 13C-i 8.25% 94.44 0.01 1.39 0.57 7.08 3.15 Months 13C-ii0.3% 93.21 0.04 1.14 0.58 8.91 4.98 3 13C-i 8.25% 92.31 0.03 2.13 0.568.53 4.60 Months 13C-ii 0.3% 90.99 0.05 1.77 0.53 10.54 6.61

The results of stability testing of Example 13C-i-ii at 55° C. are setforth in Table 133 below. TABLE 133 Lecithin Total Impurities 55° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 13C-i 8.25% 100.000.02 0.55 0.59 3.93 13C-ii 0.3% 100.00 0.03 0.53 0.59 3.93 1 13C-i 8.25%98.48 0.01 1.16 0.56 5.74 1.81 Week 13C-ii 0.3% 97.97 0.04 1.42 0.556.70 2.77 2 13C-i 8.25% 94.16 0.01 1.75 0.55 7.10 3.17 Weeks 13C-ii 0.3%96.66 0.05 2.27 0.52 8.73 4.80

EXAMPLE 13D Dronabinol Solution in Sesame Oil Sourced from Arista—Vials

In Example 13D, dronabinol formulations 13D-i, and 13D-ii were preparedin accordance with Examples 13-x and 13-ix, respectively using sesameoil sourced from Arista. Formulation 13D-i contained 8.25% lecithin andformulation 13D-ii contained 0.3% lecithin. The dronabinol formulationswere then used to amber fill glass vials. The formulations within thevials were initially tested, then tested at 25° C. for 3 and 6 months;40° C. for 1, 2 and 3 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 13D-i-ii at 25° C. are setforth in Table 134 below. TABLE 134 Lecithin Total Impurities 25° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 13D-i 8.25% 100.000.04 0.52 0.55 4.03 13D-ii 0.3% 100.00 0.01 0.49 0.53 3.67 3 13D-i 8.25%97.24 0.04 0.66 0.50 4.66 0.63 Months 13D-ii 0.3% 95.91 0.10 0.65 0.615.86 2.19 6 13D-i 8.25% 100.94 0.01 0.83 0.52 5.26 1.23 Months 13D-ii0.3% 100.23 0.01 0.83 0.52 5.26 1.23

The results of stability testing of Example 13D-i-ii at 40° C. are setforth in Table 135 below. TABLE 135 Lecithin Total Impurities 40° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 13D-i 8.25% 100.000.04 0.52 0.55 4.03 13D-ii 0.3% 100.00 0.01 0.49 0.53 3.67 1 13D-i 8.25%98.34 0.01 0.74 0.50 4.71 0.68 Month 13D-ii 0.3% 98.39 0.02 0.77 0.504.90 1.23 2 13D-i 8.25% 95.96 0.01 1.10 0.48 5.80 1.77 Months 13D-ii0.3% 94.97 0.02 1.18 0.47 6.52 2.85 3 13D-i 8.25% 94.41 0.07 1.72 0.488.18 4.15 Months 13D-ii 0.3% 93.70 0.10 1.92 0.49 8.83 5.16

The results of stability testing of Example 13D-i-ii at 55° C. are setforth in Table 136 below. TABLE 136 Lecithin Total Impurities 55° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 13D-i 8.25% 100.000.04 0.52 0.55 4.03 13D-ii 0.3% 100.00 0.01 0.49 0.53 3.67 1 13D-i 8.25%98.88 0.01 0.92 0.51 5.13 1.10 Week 13D-ii 0.3% 99.26 0.02 0.96 0.525.56 1.89 2 13D-i 8.25% 96.89 0.01 1.29 0.51 6.17 2.14 Weeks 13D-ii 0.3%95.62 0.02 1.31 0.50 6.87 3.20

EXAMPLE 13E Dronabinol Solution in Sesame Oil Sourced from Croda—Vials

In Example 13E, dronabinol formulations 13E-i, and 13E-ii were preparedin accordance with Examples 13-x and 13-ix, respectively using sesameoil sourced from Croda. Formulation 13E-i contained 8.25% lecithin andformulation 13E-ii contained 0.3% lecithin. The dronabinol formulationswere then used to fill amber glass vials. The formulations within thevials were initially tested, then tested at 25° C. for 3 and 6 months;40° C. for 1, 2 and 3 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 13E-i-ii at 25° C. are setforth in Table 137 below. TABLE 137 Lecithin Total Impurities 25° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 13E-i 8.25% 100.000.02 0.45 0.58 3.73 13E-ii 0.3% 100.00 0.04 0.42 0.56 3.67 3 13E-i 8.25%95.66 0.06 0.69 0.56 5.27 1.54 Months 13E-ii 0.3% 95.91 0.10 0.65 0.615.86 2.19 6 13E-i 8.25% 98.93 0.03 0.91 0.58 6.29 2.56 Months 13E-ii0.3% 98.55 0.08 0.92 0.59 7.34 3.67

The results of stability testing of Example 13E-i-ii at 40° C. are setforth in Table 138 below. TABLE 138 Lecithin Total Impurities 40° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 13E-i 8.25% 100.000.02 0.45 0.58 3.73 13E-ii 0.3% 100.00 0.04 0.42 0.56 3.67 1 13E-i 8.25%97.76 0.01 0.78 0.55 5.57 1.84 Month 13E-ii 0.3% 97.58 0.03 0.70 0.565.90 2.23 2 13E-i 8.25% 93.74 0.02 1.19 0.57 7.24 3.51 Months 13E-ii0.3% 92.91 0.04 1.10 0.56 8.51 4.84 3 13E-i 8.25% 91.85 0.05 0.68 0.5610.85 7.12 Months 13E-ii 0.3% 90.95 0.15 1.85 0.56 11.35 7.68

The results of stability testing of Example 13E-i-ii at 55° C. are setforth in Table 139 below. TABLE 139 Lecithin Total Impurities 55° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 13E-i 8.25% 100.000.02 0.45 0.58 3.73 13E-ii 0.3% 100.00 0.04 0.42 0.56 3.67 1 13E-i 8.25%97.01 0.03 1.25 0.58 6.43 2.70 Week 13E-ii 0.3% 88.98 0.13 2.51 0.5812.47 8.80 2 13E-i 8.25% 92.29 0.02 1.89 0.53 8.50 4.77 Weeks 13E-ii0.3% 43.06 0.16 10.13 1.19 49.26 45.59

EXAMPLE 13F Dronabinol Solution in Sesame Oil Sourced from Dipasa—Vials

In Example 13F, dronabinol formulations 13F-i, and 13F-ii were preparedin accordance with Examples 13-x and 13-ix, respectively using sesameoil sourced from Dipasa. Formulation 13F-i contained 8.25% lecithin andformulation 13F-ii contained 0.3% lecithin. The dronabinol formulationswere then used to fill amber glass vials. The formulations within thevials were initially tested, then tested at 25° C. for 3 and 6 months;40° C. for 1, 2 and 3 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 13F-i-ii at 25° C. are setforth in Table 140 below. TABLE 140 Lecithin Total Impurities 25° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 13F-i 8.25% 100.000.02 0.55 0.59 3.93 13F-ii 0.3% 100.00 0.03 0.53 0.59 3.93 3 13F-i 8.25%96.62 0.06 0.80 0.55 5.37 1.44 Months 13F-ii 0.3% 96.46 0.09 0.89 0.535.75 1.82 6 13F-i 8.25% 99.94 0.02 1.08 0.56 5.82 1.89 Months 13F-ii0.3% 100.60 0.04 1.39 0.55 6.39 2.46

The results of stability testing of Example 13F-i-ii at 40° C. are setforth in Table 141 below. TABLE 141 Lecithin Total Impurities 40° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 13F-i 8.25% 100.000.02 0.55 0.59 3.93 13F-ii 0.3% 100.00 0.03 0.53 0.59 3.93 1 13F-i 8.25%97.40 0.01 0.95 0.51 5.16 1.23 Month 13F-ii 0.3% 98.37 0.03 1.10 0.525.69 1.76 2 13F-i 8.25% 93.01 0.01 1.53 0.51 6.82 2.89 Months 13F-ii0.3% 93.86 0.03 1.98 0.53 7.85 3.92 3 13F-i 8.25% 92.48 0.12 2.53 0.5210.97 7.04 Months 13F-ii 0.3% 91.50 0.17 3.45 0.52 11.87 7.94

The results of stability testing of Example 13F-i-ii at 55° C. are setforth in Table 142 below. TABLE 142 Lecithin Total Impurities 55° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 13F-i 8.25% 100.000.02 0.55 0.59 3.93 13F-ii 0.3% 100.00 0.03 0.53 0.59 3.93 1 13F-i 8.25%98.48 0.01 1.16 0.56 5.74 1.81 Week 13F-ii 0.3% 97.97 0.04 1.42 0.556.70 2.77 2 13F-i 8.25% 94.16 0.01 1.75 0.55 7.10 3.17 Weeks 13F-ii 0.3%96.66 0.05 2.27 0.52 8.73 4.80

EXAMPLE 13G Dronabinol Solution in Sesame Oil Sourced fromArista—Capsules

In Example 13G, dronabinol formulations 13G-i, and 13G-ii were preparedin accordance with Examples 13-viii and 13-vii, respectively usingsesame oil sourced from Arista. Formulation 13F-i contained 0.1%L-ascorbic acid-6-palmitate and formulation 13G-ii contained 0.1%L-ascorbic acid-6-palmitate. The dronabinol formulations were then usedto fill hard gelatin capsules in accordance with Example 2. Theformulations within the capsules were initially tested, then tested at25° C. for 3 and 6 months; 40° C. for 1, 2 and 3 months and at 55° C.for 1 and 2 weeks.

The results of stability testing of Example 13G-i-ii at 25° C. are setforth in Table 143 below. TABLE 143 Ascorbic-palmitate Total Impurities25° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 13G-i 0.1%100.00 0.01 0.54 0.52 3.73 13G-ii 0.01% 100.00 0.02 0.50 0.51 3.10 313G-i 0.1% 97.70 0.05 0.71 0.52 4.21 0.48 Months 13G-ii 0.01% 96.30 0.050.64 0.52 4.99 1.89 6 13G-i 0.1% 100.53 0.09 0.71 0.54 4.79 1.06 Months13G-ii 0.01% 97.60 0.28 0.72 0.54 7.17 4.07

The results of stability testing of Example 13G-i-ii at 40° C. are setforth in Table 144 below. TABLE 144 Ascorbic-palmitate Total Impurities40° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 13G-i 0.1%100.00 0.01 0.54 0.52 3.73 13G-ii 0.01% 100.00 0.02 0.50 0.51 3.10 113G-i 0.1% 98.35 0.02 0.63 0.52 4.33 0.60 Month 13G-ii 0.01% 96.00 0.160.72 0.50 7.21 4.11 2 13G-i 0.1% 96.14 0.04 0.84 0.50 5.92 2.19 Months13G-ii 0.01% 90.97 0.25 0.93 0.53 10.06 6.96 3 13G-i 0.1% 93.58 0.171.34 0.52 8.34 4.61 Months 13G-ii 0.01% 88.83 0.51 1.44 0.50 12.63 9.53

The results of stability testing of Example 13G-i-ii at 55° C. are setforth in Table 145 below. TABLE 145 Ascorbic-palmitate Total Impurities55° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 13G-i 0.1%100.00 0.01 0.54 0.52 3.73 13G-ii 0.01% 100.00 0.02 0.50 0.51 3.10 113G-i 0.1% 99.29 0.04 0.71 0.51 4.30 0.57 Week 13G-ii 0.01% 99.17 0.050.62 0.49 4.59 1.49 2 13G-i 0.1% 98.19 0.01 0.88 0.53 4.69 0.96 Weeks13G-ii 0.01% 97.17 0.01 0.73 0.51 6.60 3.50

EXAMPLE 13H Dronabinol Solution in Sesame Oil Sourced fromCroda—Capsules

In Example 13H, dronabinol formulations 13H-i, and 13H-ii were preparedin accordance with Examples 13-viii and 13-vii, respectively usingsesame oil sourced from Croda. Formulation 13H-i contained 0.1%L-ascorbic acid-6-palmitate and formulation 13H-ii contained 0.1%L-ascorbic acid-6-palmitate. The dronabinol formulations were then usedto fill hard gelatin capsules in accordance with Example 2. Theformulations within the capsules were initially tested, then tested at25° C. for 3 and 6 months; 40° C. for 1, 2 and 3 months and at 55° C.for 1 and 2 weeks.

The results of stability testing of Example 13H-i-ii at 25° C. are setforth in Table 146 below. TABLE 146 Ascorbic-palmitate Total Impurities25° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 13H-i 0.1%100.00 0.03 0.48 0.56 3.85 13H-ii 0.01% 100.00 0.02 0.56 0.60 4.31 313H-i 0.1% 97.23 0.06 0.75 0.56 5.14 1.29 Months 13H-ii 0.01% 93.93 0.070.56 0.56 6.31 2.00 6 13H-i 0.1% 97.66 0.20 0.90 0.60 6.91 3.06 Months13H-ii 0.01% 98.02 0.39 0.66 0.55 8.55 4.24

The results of stability testing of Example 13H-i-ii at 40° C. are setforth in Table 147 below. TABLE 147 Ascorbic-palmitate Total Impurities40° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 13H-i 0.1%100.00 0.03 0.48 0.56 3.85 13H-ii 0.01% 100.00 0.02 0.56 0.60 4.31 113H-i 0.1% 96.37 0.06 0.76 0.54 5.98 2.13 Month 13H-ii 0.01% 88.91 0.591.09 0.56 12.48 8.17 2 13H-i 0.1% 90.81 0.21 1.09 0.60 9.76 5.91 Months13H-ii 0.01% 86.27 0.45 1.22 0.64 13.44 9.13 3 13H-i 0.1% 88.71 0.161.67 0.59 11.17 7.32 Months 13H-ii 0.01% 84.36 0.75 1.63 0.57 15.0310.72

The results of stability testing of Example 13H-i-ii at 55° C. are setforth in Table 148 below. TABLE 148 Ascorbic-palmitate Total Impurities55° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 13H-i 0.1%100.00 0.03 0.48 0.56 3.85 13H-ii 0.01% 100.00 0.02 0.56 0.60 4.31 113H-i 0.1% 95.77 0.10 0.80 0.57 6.84 2.99 Week 13H-ii 0.01% 87.54 0.120.61 0.50 15.28 10.97 2 13H-i 0.1% 91.07 0.01 1.05 0.56 11.52 7.67 Weeks13H-ii 0.01% 23.06 0.11 3.39 0.66 67.78 63.47

EXAMPLE 13I Dronabinol Solution in Sesame Oil Sourced fromDipasa—Capsules

In Example 13I, dronabinol formulations 13I-i, and 13I-ii were preparedin accordance with Examples 13-viii and 13-vii, respectively usingsesame oil sourced from Dipasa. Formulation 13I-i contained 0.1%L-ascorbic acid-6-palmitate and formulation 13I-ii contained 0.1%L-ascorbic acid-6-palmitate. The dronabinol formulations were then usedto hard gelatin capsules in accordance with Example 2. The formulationswithin the capsules were initially tested, then tested at 25° C. for 3and 6 months; 40° C. for 1, 2 and 3 months and at 55° C. for 1 and 2weeks.

The results of stability testing of Example 13I-i-ii at 25° C. are setforth in Table 149 below. TABLE 149 Ascorbic-palmitate Total Impurities25° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 13I-i 0.1%100.00 0.01 0.54 0.58 3.99 13I-ii 0.01% 100.00 0.03 0.53 0.54 3.81 313I-i 0.1% 96.89 0.02 0.84 0.55 4.52 0.53 Months 13I-ii 0.01% 95.50 0.030.69 0.53 5.72 1.91 6 13I-i 0.1% 97.83 0.13 0.94 0.56 5.79 1.80 Months13I-ii 0.01% 98.16 0.30 0.81 0.56 7.99 4.18

The results of stability testing of Example 13I-i-ii at 40° C. are setforth in Table 150 below. TABLE 150 Ascorbic-palmitate Total Impurities40° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 13I-i 0.1%100.00 0.01 0.54 0.58 3.99 13I-ii 0.01% 100.00 0.03 0.53 0.54 3.81 113I-i 0.1% 96.31 0.05 0.85 0.56 5.52 1.53 Month 13I-ii 0.01% 96.26 0.120.76 0.56 6.89 3.08 2 13I-i 0.1% 92.89 0.04 1.22 0.59 7.86 3.87 Months13I-ii 0.01% 92.24 0.24 1.01 0.61 10.03 6.22 3 13I-i 0.1% 89.96 0.121.92 0.54 10.10 6.11 Months 13I-ii 0.01% 89.56 0.36 1.53 0.54 12.04 8.23

The results of stability testing of Example 13I-i-ii at 55° C. are setforth in Table 151 below. TABLE 151 Ascorbic-palmitate Total Impurities55° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 13I-i 0.1%100.00 0.01 0.54 0.58 3.99 13I-ii 0.01% 100.00 0.03 0.53 0.54 3.81 113I-i 0.1% 96.37 0.05 0.92 0.58 5.31 1.32 Week 13I-ii 0.01% 99.37 0.060.67 0.61 5.70 1.89 2 13I-i 0.1% 93.81 0.01 1.45 0.52 8.07 4.08 Weeks13I-ii 0.01% 93.68 0.01 1.04 0.50 8.40 4.59

EXAMPLE 13J Dronabinol Solution in Sesame Oil Sourced from Arista—Vials

In Example 13J, dronabinol formulations 13J-i, and 13J-ii were preparedin accordance with Examples 13-viii and 13-vii, respectively usingsesame oil sourced from Arista. Formulation 13J-i contained 0.1%L-ascorbic acid-6-palmitate and formulation 13J-ii contained 0.1%L-ascorbic acid-6-palmitate. The dronabinol formulations were then usedto fill amber glass vials.

The formulations within the vials were initially tested, then tested at25° C. for 3 and 6 months; 40° C. for 1, 2 and 3 months and at 55° C.for 1 and 2 weeks.

The results of stability testing of Example 13J-i-ii at 25° C. are setforth in Table 152 below. TABLE 152 Ascorbic-palmitate Total Impurities25° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 13J-i 0.1%100.00 0.01 0.54 0.52 3.73 13J-ii 0.01% 100.00 0.02 0.50 0.51 3.10 313J-i 0.1% 96.55 0.12 0.76 0.49 4.84 1.11 Months 13J-ii 0.01% 95.51 0.150.68 0.52 5.49 2.39 6 13J-i 0.1% 98.93 0.13 0.98 0.50 5.75 2.02 Months13J-ii 0.01% 98.38 0.18 0.86 0.49 7.21 4.11

The results of stability testing of Example 13J-i-ii at 40° C. are setforth in Table 153 below. TABLE 153 Ascorbic-palmitate Total Impurities40° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 13J-i 0.1%100.00 0.01 0.54 0.52 3.73 13J-ii 0.01% 100.00 0.02 0.50 0.51 3.10 113J-i 0.1% 97.70 −0.04 0.76 0.50 4.36 0.63 Month 13J-ii 0.01% 97.00 0.060.68 0.50 5.49 2.39 2 13J-i 0.1% 95.10 0.08 1.05 0.50 6.06 2.33 Months13J-ii 0.01% 93.36 0.11 0.86 0.49 8.35 5.25 3 13J-i 0.1% 91.36 0.33 1.700.49 9.53 5.80 Months 13J-ii 0.01% 89.30 0.42 1.24 0.48 11.99 8.89

The results of stability testing of Example 13J-i-ii at 55° C. are setforth in Table 154 below. TABLE 154 Ascorbic-palmitate Total Impurities55° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 13J-i 0.1%100.00 0.01 0.54 0.52 3.73 13J-ii 0.01% 100.00 0.02 0.50 0.51 3.10 113J-i 0.1% 99.29 0.04 0.71 0.51 4.30 0.57 Week 13J-ii 0.01% 99.17 0.050.62 0.49 4.59 1.49 2 13J-i 0.1% 98.19 0.01 0.88 0.53 4.69 0.96 Weeks13J-ii 0.01% 97.17 0.01 0.73 0.51 6.60 3.50

EXAMPLE 13K Dronabinol Solution in Sesame Oil Sourced from Croda—Vials

In Example 13K, dronabinol formulations 13K-i, and 13K-ii were preparedin accordance with Examples 13-viii and 13-vii, respectively usingsesame oil sourced from Croda. Formulation 13K-i contained 0.1%L-ascorbic acid-6-palmitate and formulation 13K-ii contained 0.1%L-ascorbic acid-6-palmitate. The dronabinol formulations were then usedto fill amber glass vials. The formulations within the vials wereinitially tested, then tested at 25° C. for 3 and 6 months; 40° C. for1, 2 and 3 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 13K-i-ii at 25° C. are setforth in Table 155 below. TABLE 155 Ascorbic-palmitate Total Impurities25° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 13K-i 0.1%100.00 0.03 0.48 0.56 3.85 13K-ii 0.01% 100.00 0.02 0.56 0.60 4.31 313K-i 0.1% 94.37 0.23 0.63 0.57 5.77 1.92 Months 13K-ii 0.01% 92.48 0.310.52 0.58 6.59 2.28 6 13K-i 0.1% 94.76 0.20 0.86 0.62 7.88 4.03 Months13K-ii 0.01% 94.19 0.26 0.61 0.58 9.40 5.09

The results of stability testing of Example 13K-i-ii at 40° C. are setforth in Table 156 below. TABLE 156 Ascorbic-palmitate Total Impurities40° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 13K-i 0.1%100.00 0.03 0.48 0.56 3.85 13K-ii 0.01% 100.00 0.02 0.56 0.60 4.31 113K-i 0.1% 96.31 0.11 0.66 0.55 5.79 1.94 Month 13K-ii 0.01% 95.48 0.140.50 0.54 7.66 3.35 2 13K-i 0.1% 89.91 0.17 0.96 0.57 9.18 5.33 Months13K-ii 0.01% 86.82 0.22 0.62 0.58 12.53 8.22 3 13K-i 0.1% 86.06 0.731.57 0.56 14.00 10.15 Months 13K-ii 0.01% 82.08 0.19 0.97 0.53 17.6513.34

The results of stability testing of Example 13K-i-ii at 55° C. are setforth in Table 157 below. TABLE 157 Ascorbic-palmitate Total Impurities55° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 13K-i 0.1%100.00 0.03 0.48 0.56 3.85 13K-ii 0.01% 100.00 0.02 0.56 0.60 4.31 113K-i 0.1% 95.77 0.10 0.80 0.57 6.84 2.99 Week 13K-ii 0.01% 87.54 0.120.61 0.50 15.28 10.97 2 13K-i 0.1% 91.07 0.01 1.05 0.56 11.52 7.67 Weeks13K-ii 0.01% 23.06 0.11 3.39 0.66 67.78 63.47

EXAMPLE 13L Dronabinol Solution in Sesame Oil Sourced from Dipasa—Vials

In Example 13L, dronabinol formulations 13L-i, and 13L-ii were preparedin accordance with Examples 13-viii and 13-vii, respectively usingsesame oil sourced from Dipasa. Formulation 13L-i contained 0.1%L-ascorbic acid-6-palmitate and formulation 13L-ii contained 0.1%L-ascorbic acid-6-palmitate. The dronabinol formulations were then usedto fill amber glass vials.

The formulations within the vials were initially tested, then tested at25° C. for 3 and 6 months; 40° C. for 1, 2 and 3 months and at 55° C.for 1 and 2 weeks.

The results of stability testing of Example 13L-i-ii at 25° C. are setforth in Table 158 below. TABLE 158 Ascorbic-palmitate Total Impurities25° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 13L-i 0.1%100.00 0.01 0.54 0.58 3.99 13L-ii 0.01% 100.00 0.03 0.53 0.54 3.81 313L-i 0.1% 95.76 0.11 0.75 0.53 5.08 1.09 Months 13L-ii 0.01% 96.06 0.220.72 0.59 6.81 3.00 6 13L-i 0.1% 98.96 0.13 1.04 0.54 6.12 2.13 Months13L-ii 0.01% 96.94 0.19 0.96 0.53 8.82 5.01

The results of stability testing of Example 13L-i-ii at 40° C. are setforth in Table 159 below. TABLE 159 Ascorbic-palmitate Total Impurities40° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 13L-i 0.1%100.00 0.01 0.54 0.58 3.99 13L-ii 0.01% 100.00 0.03 0.53 0.54 3.81 113L-i 0.1% 98.21 0.03 0.77 0.53 4.50 0.51 Month 13L-ii 0.01% 96.57 0.150.76 0.54 6.97 3.16 2 13L-i 0.1% 93.96 0.09 1.15 0.57 6.09 2.10 Months13L-ii 0.01% 91.98 0.15 1.14 0.57 10.09 6.28 3 13L-i 0.1% 89.30 0.442.01 0.53 11.38 7.39 Months 13L-ii 0.01% 87.48 0.13 1.77 0.53 15.2511.44

The results of stability testing of Example 13L-i-ii at 55° C. are setforth in Table 160 below. TABLE 160 Ascorbic-palmitate Total Impurities55° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 13L-i 0.1%100.00 0.01 0.54 0.58 3.99 13L-ii 0.01% 100.00 0.03 0.53 0.54 3.81 113L-i 0.1% 96.37 0.05 0.92 0.58 5.31 1.32 Week 13L-ii 0.01% 99.37 0.060.67 0.61 5.70 1.89 2 13L-i 0.1% 93.81 0.01 1.45 0.52 8.07 4.08 Weeks13L-ii 0.01% 93.68 0.01 1.04 0.50 8.40 4.59

As shown from the results above, the addition of lecithin or L-ascorbicacid-6-palmitate to the dronabinol formulations helps stabilize theformulations.

The higher the concentration of anti-oxidants, the better the stabilityof dronabinol formulations. Irrespective of the source of sesame oilused, lecithin is better at stabilizing dronabinol than L-ascorbic acid.Both anti-oxidants however help in maintaining dronabinol stability.

Extended Stability Results-Combination of Degradants with Lecithin inDronabinol Formulation

In view of the stabilizing property of lecithin shown in the aboveexamples, specifically 13A-F, further studies were performed to evaluatethe effect of lecithin with the addition of degradants such as glycerin,moisture and myristic acid to dronabinol formulations stored atdifferent temperature conditions for an extended period of time.

EXAMPLE 14A Control Dronabinol Solution in Sesame Oil Sourced fromArista

In Example 14A, a dronabinol control formulation was prepared inaccordance with Example 1, using sesame oil sourced from Arista. Thedronabinol formulation was then used to fill hard gelatin capsules inaccordance with Example 2. The formulation within the capsules wasinitially tested, then tested at 25° C. for 3 and 6 months; 40° C. for1, 2, 3 and 6 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 14A at 25° C. are set forthin Table 161 below. TABLE 161 Total Impurities Control D8-THC Increase +25° C. Potency % CBD % CBN % % % % Zero 100.00 0.05 0.44 0.60 4.08 3Months 94.51 0.66 0.89 0.56 11.03 6.95 6 Months 93.26 0.72 0.98 0.5311.41 7.33

The results of stability testing of Example 14A at 40° C. are set forthin Table 162 below. TABLE 162 Total Impurities Control D8-THC Increase +40° C. Potency % CBD % CBN % % % % Zero 100.00 0.05 0.44 0.60 4.08 1Month 94.87 0.76 0.80 0.51 10.31 6.23 2 Months 94.16 0.59 1.09 0.5511.28 7.20 3 Months 94.61 0.57 1.31 0.56 12.25 8.17 6 Months 89.15 0.061.90 0.57 14.64 10.56

The results of stability testing of Example 14A at 55° C. are set forthin Table 163 below. TABLE 163 Total Impurities Control D8-THC Increase +55° C. Potency % CBD % CBN % % % % Zero 100.00 0.05 0.44 0.60 4.08 1Week 88.90 0.19 0.61 0.55 14.72 10.64 2 Weeks 71.45 2.67 1.54 0.60 27.1123.03

EXAMPLE 14B Control Dronabinol Solution in Sesame Oil Sourced from Croda

In Example 14B, a dronabinol control formulation was prepared inaccordance with Example 1, using sesame oil sourced from Croda. Thedronabinol formulation was then used to fill hard gelatin capsules inaccordance with Example 2. The formulation within the capsules wasinitially tested, then tested at 25° C. for 3 and 6 months; 40° C. for1, 2, 3 and 6 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 14B at 25° C. are set forthin Table 164 below. TABLE 164 Total Impurities Control D8-THC Increase +25° C. Potency % CBD % CBN % % % % Zero 100.00 0.03 0.77 0.81 5.53 3Months 91.48 1.01 0.62 0.61 12.51 6.98 6 Months 88.95 1.11 0.75 0.5913.64 8.11

The results of stability testing of Example 14B at 40° C. are set forthin Table 165 below. TABLE 165 Total Impurities Control D8-THC Increase +40° C. Potency % CBD % CBN % % % % Zero 100.00 0.03 0.77 0.81 5.53 1Month 87.89 1.22 0.67 0.53 12.01 6.48 2 Months 90.94 0.98 0.84 0.6112.49 6.96 3 Months 87.61 0.95 1.00 0.62 13.45 7.92 6 Months 86.92 0.611.25 0.49 14.63 9.10

The results of stability testing of Example 14B at 40° C. are set forthin Table 166 below. TABLE 166 Total Impurities Control D8-THC Increase +55° C. Potency % CBD % CBN % % % % Zero 100.00 0.03 0.77 0.81 5.53 1Week 81.35 0.26 0.69 0.58 21.10 15.57 2 Weeks 65.26 3.41 1.31 0.66 29.7024.17

EXAMPLE 14C Control Dronabinol Solution in Sesame Oil Sourced fromDipasa

In Example 14C, a dronabinol control formulation was prepared inaccordance with Example 1, using sesame oil sourced from Dipasa. Thedronabinol formulation was then used to fill hard gelatin capsules inaccordance with Example 2. The formulation within the capsules wasinitially tested, then tested at 25° C. for 3 and 6 months; 40° C. for1, 2, 3 and 6 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 14C at 25° C. are set forthin Table 167 below. TABLE 167 Total Impurities Control D8-THC Increase +25° C. Potency % CBD % CBN % % % % Zero 100.00 0.02 0.44 0.55 3.99 3Months 99.70 0.12 0.61 0.56 6.46 2.47 6 Months 97.64 0.23 0.80 0.52 8.204.21

The results of stability testing of Example 14C at 40° C. are set forthin Table 168 below. TABLE 168 Control D8- Total Impurities 40° C.Potency % CBD % CBN % THC % % Increase + % Zero 100.00 0.02 0.44 0.553.99 1 Month 95.26 0.19 0.70 0.52 6.70 2.71 2 Months 97.65 0.30 0.930.53 9.63 5.64 3 Months 95.26 0.34 1.18 0.54 11.18 7.19 6 Months 91.990.03 1.69 0.51 12.51 8.52

The results of stability testing of Example 14C at 55° C. are set forthin Table 169 below. TABLE 169 Control D8- Total Impurities 55° C.Potency % CBD % CBN % THC % % Increase + % Zero 100.00 0.02 0.44 0.553.99 1 Week 96.16 0.05 0.76 0.58 7.13 3.14 2 Weeks 92.72 0.12 1.25 0.5511.12 7.13

EXAMPLE 14D Control Dronabinol Solution in Sesame Oil Sourced fromArista

In Example 14D, a dronabinol control formulation was prepared inaccordance with Example 14A, using sesame oil sourced from Arista. Thedronabinol formulation was then used to fill amber glass vials. Theformulation within the vials was initially tested, then tested at 25° C.for 3 and 6 months; 40° C. for 1, 2, 3 and 6 months and at 55° C. for 1and 2 weeks.

The results of stability testing of Example 14D at 25° C. are set forthin Table 170 below. TABLE 170 Control D8- Total Impurities 25° C.Potency % CBD % CBN % THC % % Increase + % Zero 100.00 0.05 0.44 0.604.08 3 Months 88.57 1.54 0.77 0.52 14.79 10.71 6 Months 71.21 2.95 1.620.56 27.29 23.21

The results of stability testing of Example 14D at 40° C. are set forthin Table 171 below. TABLE 171 Control D8- Total Impurities 40° C.Potency % CBD % CBN % THC % % Increase + % Zero 100.00 0.05 0.44 0.604.08 1 Month 90.04 1.23 0.69 0.51 12.10 8.02 2 Months 81.90 2.27 1.270.50 20.62 16.54 3 Months 65.52 2.75 2.43 0.59 31.20 27.12 6 Months29.92 2.28 7.78 0.85 60.00 55.92

The results of stability testing of Example 14D at 55° C. are set forthin Table 172 below. TABLE 172 Control D8- Total Impurities 55° C.Potency % CBD % CBN % THC % % Increase + % Zero 100.00 0.05 0.44 0.604.08 1 Week 88.90 0.19 0.61 0.55 14.72 10.64 2 Weeks 71.45 2.67 1.540.60 27.11 23.03

EXAMPLE 14E Control Dronabinol Solution in Sesame Oil Sourced from Croda

In Example 14E, a dronabinol control formulation was prepared inaccordance with Example 14B, using sesame oil sourced from Croda. Thedronabinol formulation was then used to fill amber glass vials. Theformulation within the vials was initially tested, then tested at 25° C.for 3 and 6 months; 40° C. for 1, 2, 3 and 6 months and at 55° C. for 1and 2 weeks.

The results of stability testing of Example 14E at 25° C. are set forthin Table 173 below. TABLE 173 Control D8- Total Impurities 25° C.Potency % CBD % CBN % THC % % Increase + % Zero 100.00 0.03 0.77 0.815.53 3 Months 85.10 2.07 0.75 0.58 18.41 12.88 6 Months 69.68 3.38 1.180.60 30.45 24.92

The results of stability testing of Example 14E at 40° C. are set forthin Table 174 below. TABLE 174 Control D8- Total Impurities 40° C.Potency % CBD % CBN % THC % % Increase + % Zero 100.00 0.03 0.77 0.815.53 1 Month 84.66 1.64 0.69 0.56 15.97 10.44 2 Months 75.78 2.82 1.170.58 25.65 20.12 3 Months 59.02 3.54 1.89 0.56 36.06 30.53 6 Months23.92 2.88 7.00 0.89 65.24 59.71

The results of stability testing of Example 14E at 55° C. are set forthin Table 175 below. TABLE 175 Control D8- Total Impurities 55° C.Potency % CBD % CBN % THC % % Increase + % Zero 100.00 0.03 0.77 0.815.53 1 Week 81.35 0.26 0.69 0.58 21.10 15.57 2 Weeks 65.26 3.41 1.310.66 29.70 24.17

EXAMPLE 14F Control Dronabinol Solution in Sesame Oil Sourced fromDipasa

In Example 14F, a dronabinol control formulation was prepared inaccordance with Example 14C, using sesame oil sourced from Dipasa. Thedronabinol formulation was then used to fill amber glass vials. Theformulation within the vials was then tested at 25° C. for 3 and 6months; 40° C. for 1, 2, 3 and 6 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 14F at 25° C. are set forthin Table 176 below. TABLE 176 Control D8- Total Impurities 25° C.Potency % CBD % CBN % THC % % Increase + % Zero 100.00 0.02 0.44 0.553.99 3 Months 99.26 0.18 0.70 0.53 6.04 2.05 6 Months 95.28 0.38 0.940.58 9.05 5.06

The results of stability testing of Example 14F at 40° C. are set forthin Table 177 below. TABLE 177 Control D8- Total Impurities 40° C.Potency % CBD % CBN % THC % % Increase + % Zero 100.00 0.02 0.44 0.553.99 1 Month 95.74 0.23 0.81 0.51 7.12 3.13 2 Months 95.31 0.38 1.150.52 10.16 6.17 3 Months 90.52 0.39 1.76 0.53 14.04 10.05 6 Months 76.780.65 3.53 0.54 25.94 21.95

The results of stability testing of Example 14F at 55° C. are set forthin Table 178 below. TABLE 178 Control D8- Total Impurities 55° C.Potency % CBD % CBN % THC % % Increase + % Zero 100.00 0.02 0.44 0.553.99 1 Week 96.16 0.05 0.76 0.58 7.13 3.14 2 Weeks 92.72 0.12 1.25 0.5511.12 7.13

EXAMPLE 14G Dronabinol Solution in Sesame Oil Sourced from Arista withLecithin and Different Degradants Added

In Example 14G-i-iii, dronabinol formulations were prepared inaccordance with Example 14A, using sesame oil sourced from Arista, with8.25% lecithin added. Formula 14G-i also contained 0.2% glycerin;formula 14G-ii also contained 0.1% myristic acid; and formula 14G-iiicontained 100% moisture prepared in accordance with Example 6. Thedronabinol formulations were then used to fill hard gelatin capsules inaccordance with Example 2. The formulations within the capsules wereinitially tested, then tested at 25° C. for 3 and 6 months; 40° C. for1, 2, 3 and 6 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 14G-i-iii at 25° C. are setforth in Table 179 below. TABLE 179 Lecithin 8.25% Total Impurities 25°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 14G-i Glycerin100.00 0.09 0.46 0.56 3.76 0.2% 14G-ii Myristic 100.00 0.10 0.47 0.563.77 acid 0.1% 14G-iii Moisture 100.00 0.09 0.46 0.54 3.69 100% 3 M14G-i Glycerin 100.41 0.01 0.70 0.52 5.18 1.42 0.2% 14G-ii Myristic100.81 0.01 0.73 0.51 5.27 1.50 acid 0.1% 14G-iii Moisture 100.93 0.010.71 0.54 5.18 1.49 100% 6 M 14G-i Glycerin 98.62 0.01 0.83 0.49 5.451.69 0.2% 14G-ii Myristic 98.34 0.01 0.99 0.53 5.59 1.82 acid 0.1%14G-iii Moisture 99.01 0.01 0.85 0.51 5.64 1.95 100%

The results of stability testing of Example 14G-i-iii at 40° C. are setforth in Table 180 below. TABLE 180 Lecithin 8.25% Total Impurities 40°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 14G-i Glycerin100.00 0.09 0.46 0.56 3.76 0.2% 14G-ii Myristic 100.00 0.10 0.47 0.563.77 acid 0.1% 14G-iii Moisture 100.00 0.09 0.46 0.54 3.69 100% 1 M14G-i Glycerin 95.91 0.07 0.80 0.51 5.47 1.71 0.2% 14G-ii Myristic 96.580.04 0.79 0.53 5.80 2.03 acid 0.1% 14G-iii Moisture 96.38 0.02 0.79 0.525.38 1.69 100% 2 M 14G-i Glycerin 99.79 0.02 1.12 0.53 6.39 2.63 0.2%14G-ii Myristic 98.30 0.01 1.07 0.52 6.43 2.66 acid 0.1% 14G-iiiMoisture 98.42 0.02 1.10 0.48 6.57 2.88 100% 3 M 14G-i Glycerin 97.270.01 1.63 0.54 7.63 3.87 0.2% 14G-ii Myristic 96.59 0.01 1.48 0.56 7.753.98 acid 0.1% 14G-iii Moisture 96.72 0.01 1.43 0.53 8.06 4.37 100% 6 M14G-i Glycerin 93.62 0.01 2.55 0.50 9.52 5.76 0.2% 14G-ii Myristic 93.810.02 2.41 0.52 9.76 5.99 acid 0.1% 14G-iii Moisture 94.06 0.01 2.56 0.5110.08 6.39 100%

The results of stability testing of Example 14G-i-iii at 55° C. are setforth in Table 181 below. TABLE 181 Lecithin 8.25% Total Impurities 55°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 14G-i Glycerin100.00 0.09 0.46 0.56 3.76 0.2% 14G-ii Myristic 100.00 0.10 0.47 0.563.77 acid 0.1% 14G-iii Moisture 100.00 0.09 0.46 0.54 3.69 100% 1 W14G-i Glycerin 98.10 0.04 0.97 0.57 5.36 1.60 0.2% 14G-ii Myristic 97.690.02 0.89 0.60 5.25 1.48 acid 0.1% 14G-iii Moisture 99.09 0.02 0.78 0.724.86 1.17 100% 2 W 14G-i Glycerin 96.94 0.01 1.57 0.55 6.73 2.97 0.2%14G-ii Myristic 97.68 0.01 1.41 0.55 6.68 2.91 acid 0.1% 14G-iiiMoisture 98.85 0.02 1.17 0.55 5.98 2.29 100%

EXAMPLE 14H Dronabinol Solution in Sesame Oil Sourced from Croda withLecithin and Different Degradants Added

In Example 14H-i-iii, dronabinol formulations were prepared inaccordance with Example 14B, using sesame oil sourced from Croda, with8.25% lecithin added. Formula 14H-i also contained 0.2% glycerin;formula 14H-ii also contained 0.1% myristic acid; and formula 14H-iiicontained 100% moisture prepared in accordance with Example 6. Thedronabinol formulations were then used to fill hard gelatin capsules inaccordance with Example 2. The formulations within the capsules wereinitially tested, then tested at 25° C. for 3 and 6 months; 40° C. for1, 2, 3 and 6 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 14H-i-iii at 25° C. are setforth in Table 182 below. TABLE 182 Lecithin 8.25% Total Impurities 25°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 14H-i Glycerin100.00 0.05 0.47 0.56 3.52 0.2% 14H-ii Myristic 100.00 0.02 0.47 0.583.43 acid 0.1% 14H-iii Moisture 100.00 0.01 0.47 0.57 3.37 100% 3 M14H-i Glycerin 99.26 0.02 0.67 0.55 4.99 1.47 0.2% 14H-ii Myristic 97.690.01 0.68 0.56 5.24 1.81 acid 0.1% 14H-iii Moisture 99.34 0.01 0.65 0.595.26 1.89 100% 6 M 14H-i Glycerin 96.02 0.05 0.81 0.60 6.90 3.38 0.2%14H-ii Myristic 96.04 0.02 0.86 0.62 6.15 2.72 acid 0.1% 14H-iiiMoisture 92.84 0.06 1.10 0.59 8.45 5.08 100%

The results of stability testing of Example 14H-i-iii at 40° C. are setforth in Table 183 below. TABLE 183 Lecithin 8.25% Total Impurities 40°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 14H-i Glycerin100.00 0.05 0.47 0.56 3.52 0.2% 14H-ii Myristic 100.00 0.02 0.47 0.583.43 acid 0.1% 14H-iii Moisture 100.00 0.01 0.47 0.57 3.37 100% 1 M14H-i Glycerin 93.05 0.12 0.82 0.55 6.41 2.89 0.2% 14H-ii Myristic 93.650.03 0.79 0.59 5.80 2.37 acid 0.1% 14H-iii Moisture 89.84 0.05 1.30 0.598.58 5.21 100% 2 M 14H-i Glycerin 94.03 0.02 1.32 0.55 9.04 5.52 0.2%14H-ii Myristic 95.18 0.03 1.43 0.55 9.13 5.70 acid 0.1% 14H-iiiMoisture 92.78 0.06 1.62 0.55 10.00 6.63 100% 3 M 14H-i Glycerin 93.160.01 1.69 0.60 10.45 6.93 0.2% 14H-ii Myristic 90.68 0.02 1.82 0.5810.16 6.73 acid 0.1% 14H-iii Moisture 91.73 0.01 1.96 0.61 10.67 7.30100% 6 M 14H-i Glycerin 88.53 0.01 2.81 0.56 12.62 9.10 0.2% 14H-iiMyristic 88.78 0.03 2.89 0.56 12.34 8.91 acid 0.1% 14H-iii Moisture88.61 0.02 3.08 0.55 12.90 9.53 100%

The results of stability testing of Example 14H-i-iii at 55° C. are setforth in Table 184 below. TABLE 184 Lecithin 8.25% Total Impurities 55°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 14H-i Glycerin100.00 0.05 0.47 0.56 3.52 0.2% 14H-ii Myristic 100.00 0.02 0.47 0.583.43 acid 0.1% 14H-iii Moisture 100.00 0.01 0.47 0.57 3.37 100% 1 W14H-i Glycerin 90.92 0.04 2.11 0.65 8.95 5.43 0.2% 14H-ii Myristic 88.540.04 1.81 0.63 8.22 4.79 acid 0.1% 14H-iii Moisture 87.62 0.06 2.33 0.649.64 6.27 100% 2 W 14H-i Glycerin 88.34 0.01 3.63 0.61 12.60 9.08 0.2%14H-ii Myristic 89.17 0.02 2.82 0.61 10.56 7.13 acid 0.1% 14H-iiiMoisture 79.64 0.06 5.89 0.69 18.07 14.70 100%

EXAMPLE 14I Dronabinol Solution in Sesame Oil Sourced from Dipasa withLecithin and Different Degradants Added

In Example 141-i-iii, dronabinol formulations were prepared inaccordance with Example 14C, using sesame oil sourced from Croda, with8.25% lecithin added. Formula 14i-i also contained 0.2% glycerin;formula 141-ii also contained 0.1% myristic acid; and formula 141-iiicontained 100% moisture prepared in accordance with Example 6. Thedronabinol formulations were then used to fill hard gelatin capsules inaccordance with Example 2. The formulations within the capsules wereinitially tested, then tested at 25° C. for 3 and 6 months; 40° C. for1, 2, 3 and 6 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 14I-i-iii at 25° C. are setforth in Table 185 below. TABLE 185 Lecithin 8.25% Total Impurities 25°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 14I-i Glycerin100.00 0.07 0.45 0.52 3.73 0.2% 14I-ii Myristic 100.00 0.07 0.44 0.553.66 acid 0.1% 14I-iii Moisture 100.00 0.09 0.43 0.54 3.66 100% 3 M14I-i Glycerin 100.44 0.01 0.68 0.52 5.38 1.65 0.2% 14I-ii Myristic101.36 0.01 0.71 0.50 5.16 1.50 acid 0.1% 14I-iii Moisture 100.05 0.020.68 0.51 5.16 1.50 100% 6 M 14I-i Glycerin 99.55 0.08 0.74 0.49 5.952.22 0.2% 14I-ii Myristic 99.58 0.04 0.84 0.57 6.26 2.60 acid 0.1%14I-iii Moisture 97.88 0.04 0.78 0.49 5.76 2.10 100%

The results of stability testing of Example 14I-i-iii at 40° C. are setforth in Table 186 below. TABLE 186 Lecithin 8.25% Total Impurities 40°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 14I-i Glycerin100.00 0.07 0.45 0.52 3.73 0.2% 14I-ii Myristic 100.00 0.07 0.44 0.553.66 acid 0.1% 14I-iii Moisture 100.00 0.09 0.43 0.54 3.66 100% 1 M14I-i Glycerin 96.96 0.03 0.73 0.52 5.11 1.38 0.2% 14I-ii Myristic 96.620.03 0.74 0.51 5.04 1.38 acid 0.1% 14I-iii Moisture 96.07 0.04 0.77 0.505.38 1.72 100% 2 M 14I-i Glycerin 99.17 0.01 0.98 0.50 6.07 2.34 0.2%14I-ii Myristic 99.64 0.02 1.04 0.49 6.36 2.70 acid 0.1% 14I-iiiMoisture 98.35 0.08 1.01 0.47 7.11 3.45 100% 3 M 14I-i Glycerin 96.740.01 1.38 0.53 7.94 4.21 0.2% 14I-ii Myristic 97.77 0.01 1.46 0.53 8.064.40 acid 0.1% 14I-iii Moisture 95.61 0.01 1.45 0.52 8.18 4.52 100% 6 M14I-i Glycerin 93.05 0.02 2.43 0.49 10.83 7.10 0.2% 14I-ii Myristic94.10 0.01 2.81 0.52 10.92 7.26 acid 0.1% 14I-iii Moisture 92.47 0.012.64 0.51 11.36 7.70 100%

The results of stability testing of Example 14I-i-iii at 55° C. are setforth in Table 187 below. TABLE 187 Lecithin 8.25% Total Impurities 55°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 14I-i Glycerin100.00 0.07 0.45 0.52 3.73 0.2% 14I-ii Myristic 100.00 0.07 0.44 0.553.66 acid 0.1% 14I-iii Moisture 100.00 0.09 0.43 0.54 3.66 100% 1 W14I-i Glycerin 95.12 0.01 0.93 0.56 5.88 2.15 0.2% 14I-ii Myristic 99.310.01 0.94 0.58 1.70 5.36 acid 0.1% 14I-iii Moisture 97.67 0.01 0.84 0.575.02 1.36 100% 2 W 14I-i Glycerin 95.55 0.01 1.85 0.51 8.15 4.42 0.2%14I-ii Myristic 98.94 0.02 1.58 0.54 6.82 3.16 acid 0.1% 14I-iiiMoisture 96.48 0.02 1.30 0.55 6.34 2.68 100%

EXAMPLE 14J Dronabinol Solution in Sesame Oil Sourced from Arista withLecithin and Different Degradants Added

In Example 14J-i-iii, dronabinol formulations were prepared inaccordance with Example 14G-i-iii, respectively. The dronabinolformulations were then used to fill amber glass vials. The formulationswithin the vials were initially tested, then tested at 25° C. for 3 and6 months; 40° C. for 1, 2, 3 and 6 months and at 55° C. for 1 and 2weeks.

The results of stability testing of Example 14J-i-iii at 25° C. are setforth in Table 188 below. TABLE 188 Lecithin 8.25% Total Impurities 25°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 14J-i Glycerin100.00 0.09 0.46 0.56 3.76 0.2% 14J-ii Myristic 100.00 0.10 0.47 0.563.77 acid 0.1% 14J-iii Moisture 100.00 0.09 0.46 0.54 3.69 100% 3 M14J-i Glycerin 101.25 0.03 0.77 0.52 4.86 1.10 0.2% 14J-ii Myristic100.59 0.02 0.83 0.53 5.02 1.25 acid 0.1% 14J-iii Moisture 101.32 0.030.80 0.54 5.01 1.32 100% 6 M 14J-i Glycerin 98.50 0.02 0.98 0.54 5.852.09 0.2% 14J-ii Myristic 98.45 0.02 1.08 0.54 6.09 2.32 acid 0.1%14J-iii Moisture 99.38 0.02 0.98 0.55 5.90 2.21 100%

The results of stability testing of Example 14J-i-iii at 40° C. are setforth in Table 189 below. TABLE 189 Lecithin 8.25% Total Impurities 40°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 14J-i Glycerin100.00 0.09 0.46 0.56 3.76 0.2% 14J-ii Myristic 100.00 0.10 0.47 0.563.77 acid 0.1% 14J-iii Moisture 100.00 0.09 0.46 0.54 3.69 100% 1 M14J-i Glycerin 96.17 0.04 0.89 0.52 5.39 1.63 0.2% 14J-ii Myristic 95.830.04 0.95 0.50 5.52 1.75 acid 0.1% 14J-iii Moisture 96.93 0.03 0.92 0.545.15 1.46 100% 2 M 14J-i Glycerin 99.06 0.01 1.24 0.53 6.12 2.36 0.2%14J-ii Myristic 97.53 0.02 1.29 0.55 6.35 2.58 acid 0.1% 14J-iiiMoisture 98.42 0.02 1.25 0.57 6.11 2.42 100% 3 M 14J-i Glycerin 96.230.02 1.79 0.53 7.78 4.02 0.2% 14J-ii Myristic 96.52 0.02 2.00 0.53 8.244.47 acid 0.1% 14J-iii Moisture 96.49 0.01 1.81 0.54 7.88 4.19 100% 6 M14J-i Glycerin 90.81 0.10 3.54 0.59 14.45 10.69 0.2% 14J-ii Myristic90.37 0.01 4.12 0.54 13.89 10.12 acid 0.1% 14J-iii Moisture 91.84 0.053.69 0.58 14.82 11.13 100%

The results of stability testing of Example 14J-i-iii at 55° C. are setforth in Table 190 below. TABLE 190 Lecithin 8.25% Total Impurities 55°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 14J-i Glycerin100.00 0.09 0.46 0.56 3.76 0.2% 14J-ii Myristic 100.00 0.10 0.47 0.563.77 acid 0.1% 14J-iii Moisture 100.00 0.09 0.46 0.54 3.69 100% 1 W14J-i Glycerin 98.10 0.04 0.97 0.57 5.36 1.60 0.2% 14J-ii Myristic 97.690.02 0.89 0.60 5.25 1.48 acid 0.1% 14J-iii Moisture 99.09 0.02 0.78 0.724.86 1.17 100% 2 W 14J-i Glycerin 96.94 0.01 1.57 0.55 6.73 2.97 0.2%14J-ii Myristic 97.68 0.01 1.41 0.55 6.68 2.91 acid 0.1% 14J-iiiMoisture 98.85 0.02 1.17 0.55 5.98 2.29 100%

EXAMPLE 14K Dronabinol Solution in Sesame Oil Sourced from Croda withLecithin and Different Degradants Added

In Example 14K-i-iii, dronabinol formulations were prepared inaccordance with Example 14H-i-iii, respectively. The dronabinolformulations were then used to fill amber glass vials. The formulationswithin the vials were initially tested, then tested at 25° C. for 3 and6 months; 40° C. for 1, 2, 3 and 6 months and at 55° C. for 1 and 2weeks.

The results of stability testing of Example 14K-i-iii at 25° C. are setforth in Table 191 below. TABLE 191 Lecithin 8.25% Total Impurities 25°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 14K-i Glycerin100.00 0.05 0.47 0.56 3.52 0.2% 14K-ii Myristic 100.00 0.02 0.47 0.583.43 acid 0.1% 14K-iii Moisture 100.00 0.01 0.47 0.57 3.37 100% 3 M14K-i Glycerin 99.01 0.03 0.69 0.60 4.87 1.35 0.2% 14K-ii Myristic 99.050.03 0.74 0.57 4.88 1.45 acid 0.1% 14K-iii Moisture 99.78 0.03 0.72 0.574.83 1.46 100% 6 M 14K-i Glycerin 96.79 0.03 0.95 0.60 6.47 2.95 0.2%14K-ii Myristic 95.85 0.03 1.00 0.59 6.43 3.00 acid 0.1% 14K-iiiMoisture 98.03 0.03 0.92 0.58 6.17 2.80 100%

The results of stability testing of Example 14K-i-iii at 40° C. are setforth in Table 192 below. TABLE 192 Lecithin 8.25% Total Impurities 40°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 14K-i Glycerin100.00 0.05 0.47 0.56 3.52 0.2% 14K-ii Myristic 100.00 0.02 0.47 0.583.43 acid 0.1% 14K-iii Moisture 100.00 0.01 0.47 0.57 3.37 100% 1 M14K-i Glycerin 94.94 0.04 0.83 0.55 5.16 1.64 0.2% 14K-ii Myristic 93.710.03 0.88 0.57 5.57 2.14 acid 0.1% 14K-iii Moisture 95.21 0.04 0.85 0.565.50 2.13 100% 2 M 14K-i Glycerin 97.03 0.01 1.24 0.60 7.25 3.73 0.2%14K-ii Myristic 95.80 0.02 1.36 0.61 7.19 3.76 acid 0.1% 14K-iiiMoisture 95.71 0.01 1.17 0.49 6.47 3.10 100% 3 M 14K-i Glycerin 93.440.05 1.83 0.56 9.74 6.22 0.2% 14K-ii Myristic 92.41 0.03 2.08 0.57 9.616.18 acid 0.1% 14K-iii Moisture 94.02 0.02 1.88 0.59 9.32 5.95 100% 6 M14K-i Glycerin 85.96 0.03 3.93 0.58 15.24 11.72 0.2% 14K-ii Myristic84.65 0.01 4.57 0.58 16.16 12.73 acid 0.1% 14K-iii Moisture 86.74 0.014.06 0.60 15.53 12.16 100%

The results of stability testing of Example 14K-i-iii at 55° C. are setforth in Table 193 below. TABLE 193 Lecithin 8.25% Total Impurities 55°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 14K-i Glycerin100.00 0.05 0.47 0.56 3.52 0.2% 14K-ii Myristic 100.00 0.02 0.47 0.583.43 acid 0.1% 14K-iii Moisture 100.00 0.01 0.47 0.57 3.37 100% 1 W14K-i Glycerin 90.92 0.04 2.11 0.65 8.95 5.43 0.2% 14K-ii Myristic 88.540.04 1.81 0.63 8.22 4.79 acid 0.1% 14K-iii Moisture 87.62 0.06 2.33 0.649.64 6.27 100% 2 W 14K-i Glycerin 88.34 0.01 3.63 0.61 12.60 9.08 0.2%14K-ii Myristic 89.17 0.02 2.82 0.61 10.56 7.13 acid 0.1% 14K-iiiMoisture 79.64 0.06 5.89 0.69 18.07 14.70 100%

EXAMPLE 14L Dronabinol Solution in Sesame Oil Sourced from Dipasa withLecithin and Different Degradants Added

In Example 14L-i-iii, dronabinol formulations were prepared inaccordance with Example 14I-i-iii, respectively. The dronabinolformulations were then used to fill amber glass vials. The formulationswithin the vials were initially tested, then tested at 25° C. for 3 and6 months; 40° C. for 1, 2, 3 and 6 months and at 55° C. for 1 and 2weeks.

The results of stability testing of Example 14L-i-iii at 25° C. are setforth in Table 194 below. TABLE 194 Lecithin 8.25% Total Impurities 25°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 14L-i Glycerin100.00 0.07 0.45 0.52 3.73 0.2% 14L-ii Myristic 100.00 0.07 0.44 0.553.66 acid 0.1% 14L-iii Moisture 100.00 0.09 0.43 0.54 3.66 100% 3 M14L-i Glycerin 102.67 0.03 0.65 0.53 4.86 1.13 0.2% 14L-ii Myristic101.65 0.03 0.82 0.53 4.88 1.22 acid 0.1% 14L-iii Moisture 100.67 0.030.79 0.54 5.08 1.42 100% 6 M 14L-i Glycerin 100.52 0.04 0.80 0.51 6.402.67 0.2% 14L-ii Myristic 100.33 0.05 1.11 0.53 6.51 2.85 acid 0.1%14L-iii Moisture 97.76 0.04 1.03 0.54 6.55 2.89 100%

The results of stability testing of Example 14L-i-iii at 40° C. are setforth in Table 195 below. TABLE 195 Lecithin 8.25% Total Impurities 40°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 14L-i Glycerin100.00 0.07 0.45 0.52 3.73 0.2% 14L-ii Myristic 100.00 0.07 0.44 0.553.66 acid 0.1% 14L-iii Moisture 100.00 0.09 0.43 0.54 3.66 100% 1 M14L-i Glycerin 98.45 0.04 0.83 0.55 5.16 1.64 0.2% 14L-ii Myristic 96.900.04 0.97 0.52 5.33 1.67 acid 0.1% 14L-iii Moisture 95.42 0.07 0.94 0.525.34 1.68 100% 2 M 14L-i Glycerin 98.90 0.01 1.13 0.52 6.90 3.17 0.2%14L-ii Myristic 98.75 0.01 1.46 0.54 6.63 2.97 acid 0.1% 14L-iiiMoisture 97.06 0.03 1.38 0.52 6.59 2.93 100% 3 M 14L-i Glycerin 95.900.04 1.73 0.52 9.01 5.28 0.2% 14L-ii Myristic 96.62 0.02 2.31 0.52 8.765.10 acid 0.1% 14L-iii Moisture 95.46 0.02 2.15 0.52 8.71 5.05 100% 6 M14L-i Glycerin 89.33 0.08 3.90 0.51 16.39 12.66 0.2% 14L-ii Myristic89.58 0.01 4.93 0.53 15.02 11.36 acid 0.1% 14L-iii Moisture 88.35 0.064.60 0.58 17.13 13.47 100%

The results of stability testing of Example 14L-i-iii at 55° C. are setforth in Table 196 below. TABLE 196 Lecithin 8.25% Total Impurities 55°C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 14L-i Glycerin100.00 0.07 0.45 0.52 3.73 0.2% 14L-ii Myristic 100.00 0.07 0.44 0.553.66 acid 0.1% 14L-iii Moisture 100.00 0.09 0.43 0.54 3.66 100% 1 W14L-i Glycerin 95.12 0.01 0.93 0.56 5.88 2.15 0.2% 14L-ii Myristic 99.310.01 0.94 0.58 1.70 5.36 acid 0.1% 14L-iii Moisture 97.67 0.01 0.84 0.575.02 1.36 100% 2 W 14L-i Glycerin 95.55 0.01 1.85 0.51 8.15 4.42 0.2%14L-ii Myristic 98.94 0.02 1.58 0.54 6.82 3.16 acid 0.1% 14L-iiiMoisture 96.48 0.02 1.30 0.55 6.34 2.68 100%

As seen from the results above, a significant improvement in thestability of dronabinol formulations was observed when lecithin isadded. The above results indicate that lecithin imparts stability todronabinol by preventing degradation induced by excipients such asglycerin, moisture and myristic acid.

Extended Stability Results-Effect of Bases Meglumine and Ethanolamine onDronabinol Formulation Stability

In view of the stabilizing property of free bases meglumine andmonoethanolamine shown in the above examples, specifically 12A-K,further studies were performed to evaluate the effect of meglumine andmonoethanolamine with the addition of degradants such as glycerin,moisture and myristic acid to dronabinol formulations stored atdifferent temperature conditions for an extended period of time.

EXAMPLE 15A Control Dronabinol Solution in Sesame Oil Sourced fromArista

In Example 15A, a dronabinol control formulation was prepared inaccordance with Example 1, using sesame oil sourced from Arista. Thedronabinol formulation was then used to fill hard gelatin capsules inaccordance with Example 2. The formulation within the capsules wasinitially tested, then tested at 25° C. for 3 and 6 months; 40° C. for1, 2, 3 and 6 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 15A at 25° C. are set forthin Table 197 below. TABLE 197 Total Impurities Control PotencyIncrease + 25° C. % CBD % CBN % D8-THC % % % Zero 100.00 0.05 0.44 0.604.08 3 Months 94.51 0.66 0.89 0.56 11.03 6.95 6 Months 93.26 0.72 0.980.53 11.41 7.33

The results of stability testing of Example 15A at 40° C. are set forthin Table 198 below. TABLE 198 Control D8- Total Impurities 40° C.Potency % CBD % CBN % THC % % Increase + % Zero 100.00 0.05 0.44 0.604.08 1 Month 94.87 0.76 0.80 0.51 10.31 6.23 2 Months 94.16 0.59 1.090.55 11.28 7.20 3 Months 94.61 0.57 1.31 0.56 12.25 8.17 6 Months 89.150.06 1.90 0.57 14.64 10.56

The results of stability testing of Example 15A at 55° C. are set forthin Table 199 below. TABLE 199 Control D8- Total Impurities 55° C.Potency % CBD % CBN % THC % % Increase + % Zero 100.00 0.05 0.44 0.604.08 1 Week 88.90 0.19 0.61 0.55 14.72 10.64 2 Weeks 71.45 2.67 1.540.60 27.11 23.03

EXAMPLE 15B Control Dronabinol Solution in Sesame Oil Sourced from Croda

In Example 15B, a dronabinol control formulation was prepared inaccordance with Example 1, using sesame oil sourced from Croda. Thedronabinol formulation was then used to fill hard gelatin capsules inaccordance with Example 2. The formulation within the capsules wasinitially tested, then tested at 25° C. for 3 and 6 months; 40° C. for1, 2, 3 and 6 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 15B at 25° C. are set forthin Table 200 below. TABLE 200 Control D8- Total Impurities 25° C.Potency % CBD % CBN % THC % % Increase + % Zero 100.00 0.03 0.77 0.815.53 3 Months 91.48 1.01 0.62 0.61 12.51 6.98 6 Months 88.95 1.11 0.750.59 13.64 8.11

The results of stability testing of Example 15B at 40° C. are set forthin Table 201 below. TABLE 201 Control D8- Total Impurities 40° C.Potency % CBD % CBN % THC % % Increase + % Zero 100.00 0.03 0.77 0.815.53 1 Month 87.89 1.22 0.67 0.53 12.01 6.48 2 Months 90.94 0.98 0.840.61 12.49 6.96 3 Months 87.61 0.95 1.00 0.62 13.45 7.92 6 Months 86.920.61 1.25 0.49 14.63 9.10

The results of stability testing of Example 15B at 55° C. are set forthin Table 202 below. TABLE 202 Control D8- Total Impurities 55° C.Potency % CBD % CBN % THC % % Increase + % Zero 100.00 0.03 0.77 0.815.53 1 Week 81.35 0.26 0.69 0.58 21.10 15.57 2 Weeks 65.26 3.41 1.310.66 29.70 24.17

EXAMPLE 15C Control Dronabinol Solution in Sesame Oil Sourced fromDipasa

In Example 15C, a dronabinol control formulation was prepared inaccordance with Example 1, using sesame oil sourced from Dipasa. Thedronabinol formulation was then used to fill hard gelatin capsules inaccordance with Example 2. The formulation within the capsules wasinitially tested, then tested at 25° C. for 3 and 6 months; 40° C. for1, 2, 3 and 6 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 15C at 25° C. are set forthin Table 203 below. TABLE 203 Control D8- Total Impurities 25° C.Potency % CBD % CBN % THC % % Increase + % Zero 100.00 0.02 0.44 0.553.99 3 Months 99.70 0.12 0.61 0.56 6.46 2.47 6 Months 97.64 0.23 0.800.52 8.20 4.21

The results of stability testing of Example 15C at 40° C. are set forthin Table 204 below. TABLE 204 Control D8- Total Impurities 40° C.Potency % CBD % CBN % THC % % Increase + % Zero 100.00 0.02 0.44 0.553.99 1 Month 95.26 0.19 0.70 0.52 6.70 2.71 2 Months 97.65 0.30 0.930.53 9.63 5.64 3 Months 95.26 0.34 1.18 0.54 11.18 7.19 6 Months 91.990.03 1.69 0.51 12.51 8.52

The results of stability testing of Example 15C at 55° C. are set forthin Table 205 below. TABLE 205 Control D8- Total Impurities 55° C.Potency % CBD % CBN % THC % % Increase + % Zero 100.00 0.02 0.44 0.553.99 1 Week 96.16 0.05 0.76 0.58 7.13 3.14 2 Weeks 92.72 0.12 1.25 0.5511.12 7.13

EXAMPLE 15D Control Dronabinol Solution in Sesame Oil Sourced fromArista

In Example 15D, a dronabinol control formulation was prepared inaccordance with Example 15A, using sesame oil sourced from Arista. Thedronabinol formulation was then used to fill amber glass vials. Theformulation within the vials was initially tested, then tested at 25° C.for 3 and 6 months; 40° C. for 1, 2, 3 and 6 months and at 55° C. for 1and 2 weeks.

The results of stability testing of Example 15D at 25° C. are set forthin Table 206 below. TABLE 206 Control D8- Total Impurities 25° C.Potency % CBD % CBN % THC % % Increase + % Zero 100.00 0.05 0.44 0.604.08 3 Months 88.57 1.54 0.77 0.52 14.79 10.71 6 Months 71.21 2.95 1.620.56 27.29 23.21

The results of stability testing of Example 15D at 40° C. are set forthin Table 207 below. TABLE 207 Control D8- Total Impurities 40° C.Potency % CBD % CBN % THC % % Increase + % Zero 100.00 0.05 0.44 0.604.08 1 Month 90.04 1.23 0.69 0.51 12.10 8.02 2 Months 81.90 2.27 1.270.50 20.62 16.54 3 Months 65.52 2.75 2.43 0.59 31.20 27.12 6 Months29.92 2.28 7.78 0.85 60.00 55.92

The results of stability testing of Example 15D at 55° C. are set forthin Table 208 below. TABLE 208 Control D8- Total Impurities 55° C.Potency % CBD % CBN % THC % % Increase + % Zero 100.00 0.05 0.44 0.604.08 1 Week 88.90 0.19 0.61 0.55 14.72 10.64 2 Weeks 71.45 2.67 1.540.60 27.11 23.03

EXAMPLE 15E Control Dronabinol Solution in Sesame Oil Sourced from Croda

In Example 15E, a dronabinol control formulation was prepared inaccordance with Example 15B, using sesame oil sourced from Croda. Thedronabinol formulation was then used to fill amber glass vials. Theformulation within the vials was initially tested, then tested at 25° C.for 3 and 6 months; 40° C. for 1, 2, 3 and 6 months and at 55° C. for 1and 2 weeks.

The results of stability testing of Example 15E at 25° C. are set forthin Table 209 below. TABLE 209 Control D8- Total Impurities 25° C.Potency % CBD % CBN % THC % % Increase + % Zero 100.00 0.03 0.77 0.815.53 3 Months 85.10 2.07 0.75 0.58 18.41 12.88 6 Months 69.68 3.38 1.180.60 30.45 24.92

The results of stability testing of Example 15E at 40° C. are set forthin Table 210 below. TABLE 210 Control D8- Total Impurities 40° C.Potency % CBD % CBN % THC % % Increase + % Zero 100.00 0.03 0.77 0.815.53 1 Month 84.66 1.64 0.69 0.56 15.97 10.44 2 Months 75.78 2.82 1.170.58 25.65 20.12 3 Months 59.02 3.54 1.89 0.56 36.06 30.53 6 Months23.92 2.88 7.00 0.89 65.24 59.71

The results of stability testing of Example 15E at 55° C. are set forthin Table 211 below. TABLE 211 Control D8- Total Impurities 55° C.Potency % CBD % CBN % THC % % Increase + % Zero 100.00 0.03 0.77 0.815.53 1 Week 81.35 0.26 0.69 0.58 21.10 15.57 2 Weeks 65.26 3.41 1.310.66 29.70 24.17

EXAMPLE 15F Control Dronabinol Solution in Sesame Oil Sourced fromDipasa

In Example 15F, a dronabinol control formulation was prepared inaccordance with Example 15C, using sesame oil sourced from Dipasa. Thedronabinol formulation was then used to fill amber glass vials. Theformulation within the vials was initially tested, then tested at 25° C.for 3 and 6 months; 40° C. for 1, 2, 3 and 6 months and at 55° C. for 1and 2 weeks. [04621 The results of stability testing of Example 15F at25° C. are set forth in Table 212 below. TABLE 212 Control D8- TotalImpurities 25° C. Potency % CBD % CBN % THC % % Increase + % Zero 100.000.02 0.44 0.55 3.99 3 Months 99.26 0.18 0.70 0.53 6.04 2.05 6 Months95.28 0.38 0.94 0.58 9.05 5.06

The results of stability testing of Example 15F at 40° C. are set forthin Table 213 below. TABLE 213 Control D8- Total Impurities 40° C.Potency % CBD % CBN % THC % % Increase + % Zero 100.00 0.02 0.44 0.553.99 1 Month 95.74 0.23 0.81 0.51 7.12 3.13 2 Months 95.31 0.38 1.150.52 10.16 6.17 3 Months 90.52 0.39 1.76 0.53 14.04 10.05 6 Months 76.780.65 3.53 0.54 25.94 21.95

The results of stability testing of Example 15F at 55° C. are set forthin Table 214 below. TABLE 214 Control D8- Total Impurities 55° C.Potency % CBD % CBN % THC % % Increase + % Zero 100.00 0.02 0.44 0.553.99 1 Week 96.16 0.05 0.76 0.58 7.13 3.14 2 Weeks 92.72 0.12 1.25 0.5511.12 7.13

EXAMPLE 15G Dronabinol Solution in Sesame Oil Sourced from Arista withMeglumine and Different Degradants Added

In Example 15G-i-iii, dronabinol formulations were prepared inaccordance with Example 15A, using sesame oil sourced from Arista.Formula 15G-i also contained 1% meglumine and 0.2% glycerin; formula15G-ii also contained 1% meglumine and 0.1% myristic acid; and formula14G-iii also contained 0.5% meglumine and 100% moisture prepared inaccordance with Example 6. The dronabinol formulations were then used tofill hard gelatin capsules in accordance with Example 2. Theformulations within the capsules were initially tested, then tested at25° C. for 3 and 6 months; 40° C. for 1, 2, 3 and 6 months and at 55° C.for 1 and 2 weeks.

The results of stability testing of Example 15G-i-iii at 25° C. are setforth in Table 215 below. TABLE 215 Meglumine 1% Total Impurities 25° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 15G-i Glycerin 100.000.02 0.44 0.52 3.61 0.2% 15G-ii Myristic 100.00 0.03 0.44 0.54 3.66 acid0.1% 15G-iii Moisture 100.00 0.09 0.49 0.54 3.89 100%* 100.00 0.04 0.430.54 3.48 3 M 15G-i Glycerin 94.65 0.25 0.61 0.52 11.02 7.41 0.2% 15G-iiMyristic 99.42 0.03 0.52 0.52 6.06 2.40 acid 0.1% 15G-iii Moisture 94.860.52 0.57 0.55 11.06 7.17 100%* 95.84 0.28 0.58 0.54 11.24 7.76 6 M15G-i Glycerin 91.34 0.31 0.68 0.53 12.97 9.36 0.2% 15G-ii Myristic97.18 0.06 0.60 0.52 6.87 3.21 acid 0.1% 15G-iii Moisture 92.37 0.790.66 0.49 11.66 7.77 100%* 94.06 0.31 0.67 0.52 11.85 8.37*meglumine 0.5% mixture

The results of stability testing of Example 15G-i-iii at 40° C. are setforth in Table 216 below. TABLE 216 Meglumine 1% Total Impurities 40° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 15G-i Glycerin 100.000.02 0.44 0.52 3.61 0.2% 15G-ii Myristic 100.00 0.03 0.44 0.54 3.66 acid0.1% 15G-iii Moisture 100.00 0.09 0.49 0.54 3.89 100%* 100.00 0.04 0.430.54 3.48 1 M 15G-i Glycerin 90.38 0.37 0.59 0.50 11.35 7.74 0.2% 15G-iiMyristic 92.84 0.20 0.76 0.53 8.81 5.15 acid 0.1% 15G-iii Moisture 91.630.69 0.61 0.52 10.18 6.29 100%* 93.33 0.39 0.59 0.51 10.66 7.18 2 M15G-i Glycerin 91.82 0.95 0.68 0.47 14.96 11.35 0.2% 15G-ii Myristic94.73 0.17 0.93 0.52 10.23 6.57 acid 0.1% 15G-iii Moisture 93.67 0.660.72 0.52 11.12 7.23 100%* 94.03 0.32 0.69 0.49 11.77 8.29 3 M 15G-iGlycerin 91.10 0.32 0.79 0.55 13.21 9.60 0.2% 15G-ii Myristic 94.90 0.140.99 0.56 9.41 5.75 acid 0.1% 15G-iii Moisture 94.82 0.56 0.78 0.5411.32 7.43 100%* 95.63 0.30 0.74 0.54 12.08 8.60 6 M 15G-i Glycerin87.33 0.27 1.11 0.49 15.52 11.91 0.2% 15G-ii Myristic 91.93 0.19 1.360.56 11.35 7.69 acid 0.1% 15G-iii Moisture 89.59 0.50 1.14 0.50 13.579.68 100%* 90.36 0.25 1.10 0.49 14.02 10.54*meglumine 0.5% mixture

The results of stability testing of Example 15G-i-iii at 55° C. are setforth in Table 217 below. TABLE 217 Meglumine 1% Total Impurities 55° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 15G-i Glycerin 100.000.02 0.44 0.52 3.61 0.2% 15G-ii Myristic 100.00 0.03 0.44 0.54 3.66 acid0.1% 15G-iii Moisture 100.00 0.09 0.49 0.54 3.89 100%* 100.00 0.04 0.430.54 3.48 1 W 15G-i Glycerin 91.77 0.22 0.50 0.59 11.33 7.72 0.2% 15G-iiMyristic 92.63 0.33 0.73 0.60 10.66 7.00 acid 0.1% 15G-iii Moisture93.29 0.41 0.48 0.60 8.64 4.75 100%* 92.84 0.25 0.50 0.59 11.35 7.87 2 W15G-i Glycerin 90.01 0.14 0.61 0.56 12.91 9.30 0.2% 15G-ii Myristic91.29 0.24 1.03 0.56 12.21 8.55 acid 0.1% 15G-iii Moisture 86.17 1.070.75 0.56 15.44 11.55 100%* 91.65 0.16 0.59 0.52 12.98 9.50*meglumine 0.5% mixture

EXAMPLE 15H Dronabinol Solution in Sesame Oil Sourced from Croda withMeglumine and Different Degradants Added

In Example 155H-i-iii, dronabinol formulations were prepared inaccordance with Example 15B, using sesame oil sourced from Croda.Formula 15H-i also contained 1% meglumine and 0.2% glycerin; formula15H-ii also contained 1% meglumine and 0.1% myristic acid; and formula15H-iii also contained 0.5% meglumine and 100% moisture prepared inaccordance with Example 6. The dronabinol formulations were then used tofill hard gelatin capsules in accordance with Example 2. Theformulations within the capsules were initially tested, then tested at25° C. for 3 and 6 months; 40° C. for 1, 2, 3 and 6 months and at 55° C.for 1 and 2 weeks.

The results of stability testing of Example 15H-i-iii at 25° C. are setforth in Table 218 below. TABLE 218 Meglumine 1% Total Impurities 25° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 15H-i Glycerin 100.000.01 0.46 0.56 3.27 0.2% 15H-ii Myristic 100.00 0.01 0.45 0.53 3.01 acid0.1% 15H-iii Moisture 100.00 0.11 0.49 0.56 3.82 100%* 100.00 0.02 0.460.59 3.33 3 M 15H-i Glycerin 93.42 0.52 0.51 0.57 10.89 7.62 0.2% 15H-iiMyristic 89.99 0.44 0.56 0.59 11.02 8.01 acid 0.1% 15H-iii Moisture94.03 0.67 0.50 0.61 12.78 8.96 100%* 93.61 0.53 0.51 0.58 11.25 7.92 6M 15H-i Glycerin 90.96 0.68 0.52 0.57 13.55 10.28 0.2% 15H-ii Myristic88.14 0.51 0.64 0.58 12.16 9.15 acid 0.1% 15H-iii Moisture 90.79 0.870.57 0.59 13.28 9.46 100%* 90.69 0.59 0.56 0.62 13.19 9.86*meglumine 0.5% mixture

The results of stability testing of Example 15H-i-iii at 40° C. are setforth in Table 219 below. TABLE 219 Meglumine 1% Total Impurities 40° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 15H-i Glycerin 100.000.01 0.46 0.56 3.27 0.2% 15H-ii Myristic 100.00 0.01 0.45 0.53 3.01 acid0.1% 15H-iii Moisture 100.00 0.11 0.49 0.56 3.82 100%* 100.00 0.02 0.460.59 3.33 1 M 15H-i Glycerin 90.98 0.56 0.52 0.56 10.39 7.12 0.2% 15H-iiMyristic 86.93 0.40 0.68 0.58 10.36 7.35 acid 0.1% 15H-iii Moisture90.69 0.99 0.56 0.57 12.24 8.42 100%* 89.84 0.56 0.52 0.56 10.60 7.27 2M 15H-i Glycerin 91.30 0.56 0.56 0.54 11.88 8.61 0.2% 15H-ii Myristic88.90 0.39 0.85 0.57 11.52 8.51 acid 0.1% 15H-iii Moisture 92.41 0.850.57 0.55 12.78 8.96 100%* 91.42 0.51 0.56 0.56 11.34 8.01 3 M 15H-iGlycerin 91.92 0.61 0.55 0.58 12.74 9.47 0.2% 15H-ii Myristic 88.24 0.320.94 0.59 12.00 8.99 acid 0.1% 15H-iii Moisture 92.54 0.69 0.62 0.6012.56 8.74 100%* 90.70 0.44 0.57 0.61 12.34 9.01 6 M 15H-i Glycerin88.61 0.35 0.62 0.57 13.43 10.16 0.2% 15H-ii Myristic 84.71 0.18 1.190.56 13.14 10.13 acid 0.1% 15H-iii Moisture 88.90 0.58 0.75 0.56 14.0210.20 100%* 90.36 0.25 1.10 0.49 14.02 10.54*meglumine 0.5% mixture

The results of stability testing of Example 15H-i-iii at 55° C. are setforth in Table 220 below. TABLE 220 Meglumine 1% Total Impurities 55° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 15H-i Glycerin 100.000.01 0.46 0.56 3.27 0.2% 15H-ii Myristic 100.00 0.01 0.45 0.53 3.01 acid0.1% 15H-iii Moisture 100.00 0.11 0.49 0.56 3.82 100%* 100.00 0.02 0.460.59 3.33 1 W 15H-i Glycerin 83.45 0.90 0.47 0.61 16.19 12.92 0.2%15H-ii Myristic 86.65 0.45 0.65 0.64 12.53 9.52 acid 0.1% 15H-iiiMoisture 87.92 1.25 0.50 0.55 13.24 9.42 100%* 86.86 0.94 0.52 0.5915.89 12.56 2 W 15H-i Glycerin 71.10 1.85 0.68 0.59 28.07 24.80 0.2%15H-ii Myristic 78.00 0.50 1.27 0.63 19.09 16.08 acid 0.1% 15H-iiiMoisture 78.81 2.50 0.67 0.59 22.93 19.11 100%* 73.45 1.22 0.73 0.5826.08 22.75*meglumine 0.5% mixture

EXAMPLE 15I Dronabinol Solution in Sesame Oil Sourced from Dipasa withMeglumine and Different Degradants Added

In Example 15I-i-iii, dronabinol formulations were prepared inaccordance with Example 15C, using sesame oil sourced from Dipasa.Formula 15I-i also contained 1% meglumine and 0.2% glycerin; formula15I-ii also contained 1% meglumine and 0.1% myristic acid; and formula15I-iii also contained 0.5% meglumine and 100% moisture prepared inaccordance with Example 6. The dronabinol formulations were then used tofill hard gelatin capsules in accordance with Example 2. Theformulations within the capsules were initially tested, then tested at25° C. for 3 and 6 months; 40° C. for 1, 2, 3 and 6 months and at 55° C.for 1 and 2 weeks.

The results of stability testing of Example 15I-i-iii at 25° C. are setforth in Table 221 below. TABLE 221 Meglumine 1% Total Impurities 25° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 15I-i Glycerin 100.000.02 0.43 0.54 3.68 0.2% 15I-ii Myristic 100.00 0.02 0.42 0.52 3.65 acid0.1% 15I-iii Moisture 100.00 0.05 0.44 0.50 3.61 100%* 100.00 0.09 0.410.52 3.63 3 M 15I-i Glycerin 100.59 0.04 0.49 0.51 6.10 2.42 0.2% 15I-iiMyristic 99.78 0.03 0.51 0.52 5.49 1.84 acid 0.1% 15I-iii Moisture 95.290.19 0.52 0.55 7.76 4.15 100%* 99.41 0.04 0.49 0.53 5.66 2.03 6 M 15I-iGlycerin 99.06 0.06 0.55 0.53 6.58 2.90 0.2% 15I-ii Myristic 97.46 0.050.61 0.51 6.21 2.56 acid 0.1% 15I-iii Moisture 93.42 0.36 0.60 0.51 8.655.04 100%* 98.88 0.07 0.57 0.55 6.36 2.73*meglumine 0.5% mixture

The results of stability testing of Example 15I-i-iii at 40° C. are setforth in Table 222 below. TABLE 222 Meglumine 1% Total Impurities 40° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 15I-i Glycerin 100.000.02 0.43 0.54 3.68 0.2% 15I-ii Myristic 100.00 0.02 0.42 0.52 3.65 acid0.1% 15I-iii Moisture 100.00 0.05 0.44 0.50 3.61 100%* 100.00 0.09 0.410.52 3.63 1 M 15I-i Glycerin 96.48 0.08 0.52 0.51 6.40 2.72 0.2% 15I-iiMyristic 95.70 0.08 0.54 0.51 6.05 2.40 acid 0.1% 15I-iii Moisture 91.740.37 0.58 0.52 7.81 4.20 100%* 96.13 0.07 0.51 0.52 6.04 2.41 2 M 15I-iGlycerin 97.24 0.06 0.62 0.50 7.77 4.09 0.2% 15I-ii Myristic 97.54 0.060.71 0.51 7.01 3.36 acid 0.1% 15I-iii Moisture 94.46 0.31 0.66 0.52 8.454.84 100%* 97.04 0.06 0.60 0.51 7.29 3.66 3 M 15I-i Glycerin 96.60 0.080.72 0.54 9.07 5.39 0.2% 15I-ii Myristic 95.22 0.08 0.86 0.54 8.63 4.98acid 0.1% 15I-iii Moisture 94.42 0.29 0.70 0.55 8.54 4.93 100%* 95.980.08 0.70 0.53 8.80 5.17 6 M 15I-i Glycerin 92.16 0.09 1.05 0.50 10.566.88 0.2% 15I-ii Myristic 91.93 0.19 1.36 0.56 11.35 7.69 acid 0.1%15I-iii Moisture 89.59 0.50 1.14 0.50 13.57 9.68 100%* 90.36 0.25 1.100.49 14.02 10.54*meglumine 0.5% mixture

The results of stability testing of Example 15I-i-iii at 55° C. are setforth in Table 223 below. TABLE 223 Meglumine 1% Total Impurities 55° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 15I-i Glycerin 100.000.02 0.43 0.54 3.68 0.2% 15I-ii Myristic 100.00 0.02 0.42 0.52 3.65 acid0.1% 15I-iii Moisture 100.00 0.05 0.44 0.50 3.61 100%* 100.00 0.09 0.410.52 3.63 1 W 15I-i Glycerin 93.45 0.02 0.45 0.56 6.41 2.73 0.2% 15I-iiMyristic 94.85 0.09 0.52 0.59 5.74 2.09 acid 0.1% 15I-iii Moisture 91.740.44 0.46 0.59 8.36 4.75 100%* 99.04 0.06 0.44 0.58 5.40 1.77 2 W 15I-iGlycerin 94.27 0.03 0.56 0.53 8.21 4.53 0.2% 15I-ii Myristic 96.02 0.030.71 0.51 7.08 3.43 acid 0.1% 15I-iii Moisture 85.55 0.88 0.65 0.5714.47 10.86 100%* 97.15 0.01 0.49 0.51 6.59 2.96*meglumine 0.5% mixture

EXAMPLE 15J Dronabinol Solution in Sesame Oil Sourced from Arista withMeglumine and Different Degradants Added

In Example 15J-i-iii, dronabinol formulations were prepared inaccordance with Example 15G-i-iii, respectively. The dronabinolformulations were then used to fill amber glass vials. The formulationswithin the vials were initially tested, then tested at 25° C. for 3 and6 months; 40° C. for 1, 2, 3 and 6 months and at 55° C. for 1 and 2weeks.

The results of stability testing of Example 15J-i-iii at 25° C. are setforth in Table 224 below. TABLE 224 Meglumine 1% Total Impurities 25° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 15J-i Glycerin 100.000.02 0.44 0.52 3.61 0.2% 15J-ii Myristic 100.00 0.03 0.44 0.54 3.66 acid0.1% 15J-iii Moisture 100.00 0.09 0.49 0.54 3.89 100%* 100.00 0.04 0.430.54 3.48 3 M 15J-i Glycerin 98.85 0.09 0.53 0.51 7.10 3.49 0.2% 15J-iiMyristic 101.15 0.10 0.53 0.51 5.30 1.64 acid 0.1% 15J-iii Moisture94.21 0.94 0.57 0.53 10.43 6.54 100%* 101.23 0.06 0.51 0.53 5.36 1.88 6M 15J-i Glycerin 96.89 0.07 0.55 0.52 8.29 4.68 0.2% 15J-ii Myristic99.23 0.12 0.57 0.53 6.49 2.83 acid 0.1% 15J-iii Moisture 80.16 1.970.83 0.52 27.01 23.12 100%* 99.75 0.09 0.53 0.53 6.50 3.02*meglumine 0.5% mixture

The results of stability testing of Example 15J-i-iii at 40° C. are setforth in Table 225 below. TABLE 225 Meglumine 1% Total Impurities 40° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 15J-i Glycerin 100.000.02 0.44 0.52 3.61 0.2% 15J-ii Myristic 100.00 0.03 0.44 0.54 3.66 acid0.1% 15J-iii Moisture 100.00 0.09 0.49 0.54 3.89 100%* 100.00 0.04 0.430.54 3.48 1 M 15J-i Glycerin 94.69 0.29 0.54 0.49 7.93 4.32 0.2% 15J-iiMyristic 95.29 0.05 0.55 0.51 5.75 2.09 acid 0.1% 15J-iii Moisture 90.450.61 0.60 0.52 11.21 7.32 100%* 94.68 0.05 0.51 0.52 6.23 2.75 2 M 15J-iGlycerin 96.23 0.13 0.60 0.55 9.61 6.00 0.2% 15J-ii Myristic 97.06 0.030.64 0.56 6.89 3.23 acid 0.1% 15J-iii Moisture 87.52 0.87 0.89 0.5015.69 11.80 100%* 98.99 0.06 0.53 0.55 7.39 3.91 3 M 15J-i Glycerin94.15 0.13 0.68 0.53 10.62 7.01 0.2% 15J-ii Myristic 96.69 0.02 0.840.52 8.35 4.69 acid 0.1% 15J-iii Moisture 76.29 1.16 1.37 0.55 22.7718.88 100%* 97.55 0.04 0.64 0.53 9.12 5.64 6 M 15J-i Glycerin 88.48 0.171.03 0.56 14.89 11.28 0.2% 15J-ii Myristic 91.09 0.21 1.85 0.78 15.2211.56 acid 0.1% 15J-iii Moisture 48.13 1.61 3.55 0.68 43.37 39.48 100%*90.73 0.06 0.98 0.53 13.48 10.00*meglumine 0.5% mixture

The results of stability testing of Example 15J-i-iii at 55° C. are setforth in Table 226 below. TABLE 226 Meglumine 1% Total Impurities 55° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 15J-i Glycerin 100.000.02 0.44 0.52 3.61 0.2% 15J-ii Myristic 100.00 0.03 0.44 0.54 3.66 acid0.1% 15J-iii Moisture 100.00 0.09 0.49 0.54 3.89 100%* 100.00 0.04 0.430.54 3.48 1 W 15J-i Glycerin 91.77 0.22 0.50 0.59 11.33 7.72 0.2% 15J-iiMyristic 92.63 0.33 0.73 0.60 10.66 7.00 acid 0.1% 15J-iii Moisture93.29 0.41 0.48 0.60 8.64 4.75 100%* 92.84 0.25 0.50 0.59 11.35 7.87 2 W15J-i Glycerin 90.01 0.14 0.61 0.56 12.91 9.30 0.2% 15J-ii Myristic91.29 0.24 1.03 0.56 12.21 8.55 acid 0.1% 15J-iii Moisture 86.17 1.070.75 0.56 15.44 11.55 100%* 91.65 0.16 0.59 0.52 12.98 9.50*meglumine 0.5% mixture

EXAMPLE 15K Dronabinol Solution in Sesame Oil Sourced from Croda withMeglumine and Different Degradants Added

In Example 15K-i-iii, dronabinol formulations were prepared inaccordance with Example 15H-i-iii, respectively. The dronabinolformulations were then used to fill amber glass vials. The formulationswithin the vials were initially tested, then tested at 25° C. for 3 and6 months; 40° C. for 1, 2, 3 and 6 months and at 55° C. for 1 and 2weeks.

The results of stability testing of Example 15K-i-iii at 25° C. are setforth in Table 227 below. TABLE 227 Meglumine 1% Total Impurities 25° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 15K-i Glycerin 100.000.01 0.46 0.56 3.27 0.2% 15K-ii Myristic 100.00 0.01 0.45 0.53 3.01 acid0.1% 15K-iii Moisture 100.00 0.11 0.49 0.56 3.82 100%* 100.00 0.02 0.460.59 3.33 3 M 15K-i Glycerin 90.75 0.73 0.54 0.59 12.50 9.23 0.2% 15K-iiMyristic 91.94 0.31 0.55 0.57 8.89 5.88 acid 0.1% 15K-iii Moisture 89.642.09 0.71 0.65 15.63 11.81 100%* 94.32 0.34 0.53 0.58 10.59 7.26 6 M15K-i Glycerin 78.64 1.84 0.69 0.59 24.09 20.82 0.2% 15K-ii Myristic89.29 0.22 0.58 0.58 11.45 8.44 acid 0.1% 15K-iii Moisture 72.69 2.900.75 0.58 28.54 24.72 100%* 91.50 0.44 0.58 0.55 14.26 10.93*meglumine 0.5% mixture

The results of stability testing of Example 15K-i-iii at 40° C. are setforth in Table 228 below. TABLE 228 Meglumine 1% Total Impurities 40° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 15K-i Glycerin 100.000.01 0.46 0.56 3.27 0.2% 15K-ii Myristic 100.00 0.01 0.45 0.53 3.01 acid0.1% 15K-iii Moisture 100.00 0.11 0.49 0.56 3.82 100%* 100.00 0.02 0.460.59 3.33 1 M 15K-i Glycerin 90.51 0.65 0.54 0.54 10.99 7.72 0.2% 15K-iiMyristic 87.95 0.63 0.62 0.58 10.51 7.50 acid 0.1% 15K-iii Moisture85.62 1.26 0.56 0.56 16.64 12.82 100%* 87.93 0.92 0.57 0.57 13.58 10.252 M 15K-i Glycerin 82.69 1.03 0.67 0.64 17.19 13.92 0.2% 15K-ii Myristic87.62 0.30 0.75 0.57 12.31 9.30 acid 0.1% 15K-iii Moisture 79.89 1.840.73 0.55 23.38 19.56 100%* 82.01 1.02 0.68 0.59 18.39 15.06 3 M 15K-iGlycerin 68.38 1.56 0.98 0.59 29.97 26.70 0.2% 15K-ii Myristic 85.690.26 0.94 0.58 14.45 11.44 acid 0.1% 15K-iii Moisture 65.11 2.18 1.150.60 34.06 30.24 100%* 70.46 0.99 0.97 0.59 28.49 25.16 6 M 15K-iGlycerin 50.72 1.00 1.80 0.73 41.84 38.57 0.2% 15K-ii Myristic 77.220.25 1.66 0.59 20.82 17.81 acid 0.1% 15K-iii Moisture 36.15 1.50 3.710.75 57.00 53.18 100%* 59.43 0.75 1.67 0.62 36.68 33.35*meglumine 0.5% mixture

The results of stability testing of Example 15K-i-iii at 55° C. are setforth in Table 229 below. TABLE 229 Meglumine 1% Total Impurities 55° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 15K-i Glycerin 100.000.01 0.46 0.56 3.27 0.2% 15K-ii 100.00 0.01 0.45 0.53 3.01 Myristic acid0.1% 15K-iii Moisture 100.00 0.11 0.49 0.56 3.82 100%* 100.00 0.02 0.460.59 3.33 1 W 15K-i Glycerin 83.45 0.90 0.47 0.61 16.19 12.92 0.2%15K-ii 86.65 0.45 0.65 0.64 12.53 9.52 Myristic acid 0.1% 15K-iiiMoisture 87.92 1.25 0.50 0.55 13.24 9.42 100%* 86.86 0.94 0.52 0.5915.89 12.56 2 W 15K-i Glycerin 71.10 1.85 0.68 0.59 28.07 24.80 0.2%15K-ii 78.00 0.50 1.27 0.63 19.09 16.08 Myristic acid 0.1% 15K-iiiMoisture 78.81 2.50 0.67 0.59 22.93 19.11 100%* 73.45 1.22 0.73 0.5826.08 22.75*meglumine 0.5% mixture

EXAMPLE 15L Dronabinol Solution in Sesame Oil Sourced from Dipasa withMeglumine and Different Degradants Added

In Example 15L-i-iii, dronabinol formulations were prepared inaccordance with Example 15I-i-iii, respectively. The dronabinolformulations were then used to fill amber glass vials. The formulationswithin the vials were initially tested, then tested at 25° C. for 3 and6 months; 40° C. for 1, 2, 3 and 6 months and at 55° C. for 1 and 2weeks.

The results of stability testing of Example 15L-i-iii at 25° C. are setforth in Table 230 below. TABLE 230 Meglumine 1% Total Impurities 25° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 15L-i Glycerin 100.000.02 0.43 0.54 3.68 0.2% 15L-ii Myristic 100.00 0.02 0.42 0.52 3.65 acid0.1% 15L-iii Moisture 100.00 0.05 0.44 0.50 3.61 100%* 100.00 0.09 0.410.52 3.63 3 M 15L-i Glycerin 99.49 0.07 0.49 0.52 5.12 1.44 0.2% 15L-iiMyristic 100.55 0.05 0.51 0.51 5.31 1.66 acid 0.1% 15L-iii Moisture94.65 0.53 0.55 0.52 7.88 4.27 100%* 99.80 0.05 0.49 0.51 4.86 1.23 6 M15L-i Glycerin 96.65 0.07 0.50 0.51 6.65 2.97 0.2% 15L-ii Myristic 98.800.07 0.56 0.52 6.39 2.74 acid 0.1% 15L-iii Moisture 85.81 1.13 0.74 0.5413.52 9.91 100%* 99.45 0.07 0.52 0.53 6.14 2.51*meglumine 0.5% mixture

The results of stability testing of Example 15L-i-iii at 40° C. are setforth in Table 231 below. TABLE 231 Meglumine 1% Total Impurities 40° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 15L-i Glycerin 100.000.02 0.43 0.54 3.68 0.2% 15L-ii Myristic 100.00 0.02 0.42 0.52 3.65 acid0.1% 15L-iii Moisture 100.00 0.05 0.44 0.50 3.61 100%* 100.00 0.09 0.410.52 3.63 1 M 15L-i Glycerin 96.18 0.16 0.51 0.53 6.00 2.32 0.2% 15L-iiMyristic 96.75 0.18 0.55 0.51 5.88 2.23 acid 0.1% 15L-iii Moisture 91.570.54 0.59 0.52 9.24 5.63 100%* 94.96 0.05 0.51 0.50 5.74 2.11 2 M 15L-iGlycerin 97.76 0.11 0.55 0.51 6.92 3.24 0.2% 15L-ii Myristic 98.57 0.120.75 0.50 6.55 2.90 acid 0.1% 15L-iii Moisture 86.87 1.21 0.94 0.4414.27 10.66 100%* 98.93 0.10 0.55 0.53 6.78 3.15 3 M 15L-i Glycerin95.42 0.01 0.65 0.52 8.18 4.50 0.2% 15L-ii Myristic 96.53 0.12 0.92 0.598.42 4.77 acid 0.1% 15L-iii Moisture 72.19 1.61 1.55 0.56 24.33 20.72100%* 97.28 0.02 0.68 0.50 8.00 4.37 6 M 15L-i Glycerin 89.68 0.12 1.060.59 13.79 10.11 0.2% 15L-ii Myristic 90.82 0.13 1.65 0.58 12.50 8.85acid 0.1% 15L-iii Moisture 39.64 1.54 4.95 0.70 51.32 47.71 100%* 91.650.06 1.09 0.52 12.41 8.78*meglumine 0.5% mixture

The results of stability testing of Example 15L-i-iii at 55° C. are setforth in Table 232 below. TABLE 232 Meglumine 1% Total Impurities 55° C.Potency % CBD % CBN % D8-THC % % Increase + % Zero 15L-i Glycerin 100.000.02 0.43 0.54 3.68 0.2% 15L-ii Myristic 100.00 0.02 0.42 0.52 3.65 acid0.1% 15L-iii Moisture 100.00 0.05 0.44 0.50 3.61 100%* 100.00 0.09 0.410.52 3.63 1 W 15L-i Glycerin 93.45 0.02 0.45 0.56 6.41 2.73 0.2% 15L-iiMyristic 94.85 0.09 0.52 0.59 5.74 2.09 acid 0.1% 15L-iii Moisture 91.740.44 0.46 0.59 8.36 4.75 100%* 99.04 0.06 0.44 0.58 5.40 1.77 2 W 15L-iGlycerin 94.27 0.03 0.56 0.53 8.21 4.53 0.2% 15L-ii Myristic 96.02 0.030.71 0.51 7.08 3.43 acid 0.1% 15L-iii Moisture 85.55 0.88 0.65 0.5714.47 10.86 100%* 97.15 0.01 0.49 0.51 6.59 2.96*meglumine 0.5% mixture

EXAMPLE 15M Dronabinol Solution in Sesame Oil Sourced from Arista withMonoethanolamine and Different Degradants Added

In Example 15M-i-iii, dronabinol formulations were prepared inaccordance with Example 15A, using sesame oil sourced from Arista with0.5% monoethanolamine added. Formula 15M-i also contained 0.2% glycerin;formula 15M-ii also contained 0.1% myristic acid; and formula 15M-iiialso contained 100% moisture prepared in accordance with Example 6. Thedronabinol formulations were then used to fill hard gelatin capsules inaccordance with Example 2. The formulations within the capsules wereinitially tested, then tested at 25° C. for 3 and 6 months; 40° C. for1, 2, 3 and 6 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 15M-i-iii at 25° C. are setforth in Table 233 below. TABLE 233 Monoethanolamine 0.5% TotalImpurities 25° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero15M-i Glycerin 100.00 0.12 0.49 0.53 4.08 0.2% 15M-ii Myristic acid100.00 0.22 0.71 0.52 4.21 0.1% 15M-iii Moisture 100.00 0.16 0.49 0.564.23 100% 3 M 15M-i Glycerin 98.45 0.26 0.83 0.54 5.95 1.87 0.2% 15M-iiMyristic acid 99.31 0.29 1.11 0.55 6.33 2.12 0.1% 15M-iii Moisture 95.610.37 0.80 0.54 11.01 6.78 100% 6 M 15M-i Glycerin 98.64 0.11 1.12 0.525.78 1.70 0.2% 15M-ii Myristic acid 99.25 0.13 1.38 0.54 6.24 2.03 0.1%15M-iii Moisture 93.82 0.57 1.12 0.54 12.55 8.32 100%

The results of stability testing of Example 15M-i-iii at 40° C. are setforth in Table 234 below. TABLE 234 Monoethanolamine 0.5% TotalImpurities 40° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero15M-i Glycerin 100.00 0.12 0.49 0.53 4.08 0.2% 15M-ii Myristic acid100.00 0.22 0.71 0.52 4.21 0.1% 15M-iii Moisture 100.00 0.16 0.49 0.564.23 100% 1 M 15M-i Glycerin 93.90 0.14 0.92 0.54 6.50 2.42 0.2% 15M-iiMyristic acid 94.33 0.27 1.20 0.53 6.89 2.68 0.1% 15M-iii Moisture 91.750.81 0.99 0.49 11.23 7.00 100% 2 M 15M-i Glycerin 97.91 0.12 1.26 0.506.34 2.26 0.2% 15M-ii Myristic acid 99.19 0.19 1.55 0.50 6.05 1.84 0.1%15M-iii Moisture 93.03 0.62 1.39 0.55 12.32 8.09 100% 3 M 15M-i Glycerin97.81 0.08 1.54 0.54 6.11 2.03 0.2% 15M-ii Myristic acid 98.95 0.09 1.590.52 5.24 1.03 0.1% 15M-iii Moisture 93.24 0.66 1.66 0.55 13.34 9.11100% 6 M 15M-i Glycerin 94.67 0.03 2.04 0.50 6.49 2.41 0.2% 15M-iiMyristic acid 97.22 0.01 2.05 0.47 6.57 2.36 0.1% 15M-iii Moisture 89.650.13 2.46 0.63 15.64 11.41 100%

The results of stability testing of Example 15M-i-iii at 55° C. are setforth in Table 235 below. TABLE 235 Monoethanolamine 0.5% TotalImpurities 55° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero15M-i Glycerin 100.00 0.12 0.49 0.53 4.08 0.2% 15M-ii Myristic acid100.00 0.22 0.71 0.52 4.21 0.1% 15M-iii Moisture 100.00 0.16 0.49 0.564.23 100% 1 W 15M-i Glycerin 96.64 0.15 0.86 0.59 5.53 1.45 0.2% 15M-iiMyristic acid 97.85 0.06 1.11 0.62 5.70 1.49 0.1% 15M-iii Moisture 95.510.02 0.62 0.59 8.55 4.32 100% 2 W 15M-i Glycerin 95.94 0.23 1.18 0.546.72 2.64 0.2% 15M-ii Myristic acid 97.85 0.32 1.57 0.52 6.87 2.66 0.1%15M-iii Moisture 94.83 0.34 0.93 0.57 10.24 6.01 100%

EXAMPLE 15N Dronabinol Solution in Sesame Oil Sourced from Croda withMonoethanolamine and Different Degradants Added

In Example 15N-i-iii, dronabinol control formulations were prepared inaccordance with Example 15B, using sesame oil sourced from Croda with0.5% monoethanolamine added. Formula 15N-i also contained 0.2% glycerin;formula 15N-ii also contained 0.1% myristic acid; and formula 15N-iiialso contained 100% moisture prepared in accordance with Example 6. Thedronabinol formulations were then used to fill hard gelatin capsules inaccordance with Example 2. The formulations within the capsules wereinitially tested, then tested at 25° C. for 3 and 6 months; 40° C. for1, 2, 3 and 6 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 15N-i-iii at 25° C. are setforth in Table 236 below. TABLE 236 Monoethanolamine 0.5% TotalImpurities 25° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero15N-i Glycerin 100.00 0.11 0.60 0.57 3.72 0.2% 15N-ii Myristic acid100.00 0.11 0.66 0.54 4.02 0.1% 15N-iii Moisture 100.00 0.10 0.58 0.573.53 100% 3 M 15N-i Glycerin 98.36 0.38 0.98 0.58 6.57 2.85 0.2% 15N-iiMyristic acid 97.48 0.22 1.20 0.58 6.47 2.45 0.1% 15N-iii Moisture 94.370.58 0.68 0.57 12.80 9.27 100% 6 M 15N-i Glycerin 98.21 0.11 1.20 0.596.31 2.59 0.2% 15N-ii Myristic acid 97.15 0.05 1.49 0.56 6.16 2.14 0.1%15N-iii Moisture 90.25 0.77 0.88 0.55 14.08 10.55 100%

The results of stability testing of Example 15N-i-iii at 40° C. are setforth in Table 237 below. TABLE 237 Monoethanolamine 0.5% TotalImpuirities 40° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero15N-i Glycerin 100.00 0.11 0.60 0.57 3.72 0.2% 15N-ii Myristic acid100.00 0.11 0.66 0.54 4.02 0.1% 15N-iii Moisture 100.00 0.10 0.58 0.573.53 100% 1 M 15N-i Glycerin 93.59 0.17 1.15 0.56 6.73 3.01 0.2% 15N-iiMyristic acid 93.54 0.10 1.38 0.57 6.68 2.66 0.1% 15N-iii Moisture 90.080.90 0.79 0.50 12.48 8.95 100% 2 M 15N-i Glycerin 94.96 0.16 1.49 0.577.26 3.54 0.2% 15N-ii Myristic acid 95.56 0.11 1.70 0.58 7.22 3.20 0.1%15N-iii Moisture 90.30 0.65 0.94 0.51 12.75 9.22 100% 3 M 15N-i Glycerin97.25 0.11 1.62 0.59 6.96 3.24 0.2% 15N-ii Myristic acid 95.74 0.17 1.830.60 7.43 3.41 0.1% 15N-iii Moisture 91.70 0.72 1.25 0.54 14.07 10.54100% 6 M 15N-i Glycerin 94.46 0.05 2.23 0.56 8.03 4.31 0.2% 15N-iiMyristic acid 94.00 0.12 2.63 0.54 8.31 4.29 0.1% 15N-iii Moisture 87.950.45 1.82 0.51 15.94 12.41 100%

The results of stability testing of Example 15N-i-iii at 55° C. are setforth in Table 238 below. TABLE 238 Monoethanolamine 0.5% TotalImpurities 55° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero15N-i Glycerin 100.00 0.11 0.60 0.57 3.72 0.2% 15N-ii Myristic acid100.00 0.11 0.66 0.54 4.02 0.1% 15N-iii Moisture 100.00 0.10 0.58 0.573.53 100% 1 W 15N-i Glycerin 96.45 0.16 0.96 0.62 6.63 2.91 0.2% 15N-iiMyristic acid 95.76 0.29 1.09 0.61 6.19 2.17 15N-iii Moisture 89.20 0.080.61 0.64 14.06 10.53 100% 2 W 15N-i Glycerin 94.40 0.32 1.40 0.59 7.804.08 0.2% 15N-ii Myristic acid 95.41 0.13 1.53 0.59 7.54 3.52 0.1%15N-iii Moisture 89.05 0.53 0.86 0.64 16.18 12.65 100%

EXAMPLE 15O Dronabinol Solution in Sesame Oil Sourced from Dipasa withMonoethanolamine and Different Degradants Added

In Example 15O-i-iii, dronabinol formulations were prepared inaccordance with Example 15C, using sesame oil sourced from Dipasa with0.5% monoethanolamine added. Formula 15O-i also contained 0.2% glycerin;formula 15O-ii also contained 0.1% myristic acid; and formula 15O-iiialso contained 100% moisture prepared in accordance with Example 6. Thedronabinol formulations were then used to fill hard gelatin capsules inaccordance with Example 2. The formulations within the capsules wereinitially tested, then tested at 25° C. for 3 and 6 months; 40° C. for1, 2, 3 and 6 months and at 55° C. for 1 and 2 weeks.

The results of stability testing of Example 15O-i-iii at 25° C. are setforth in Table 239 below. TABLE 239 Monoethanolamine 0.5% TotalImpurities 25° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero15O-i Glycerin 100.00 0.17 0.48 0.49 4.13 0.2% 15O-ii Myristic acid100.00 0.14 0.52 0.47 3.99 0.1% 15O-iii Moisture 100.00 0.15 0.48 0.513.91 100% 3 M 15O-i Glycerin 97.95 0.39 0.83 0.53 6.40 2.27 0.2% 15O-iiMyristic acid 99.03 0.22 0.97 0.52 5.80 1.81 0.1% 15O-iii Moisture100.67 0.13 0.60 0.55 6.38 2.47 100% 6 M 15O-i Glycerin 97.89 0.15 1.100.52 5.91 1.78 0.2% 15O-ii Myristic acid 98.49 0.05 1.28 0.52 6.09 2.100.1% 15O-iii Moisture 98.36 0.23 0.80 0.53 7.79 3.88 100%

The results of stability testing of Example 15O-i-iii at 40° C. are setforth in Table 240 below. TABLE 240 Monoethanolamine 0.5% TotalImpurities 40° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero15O-i Glycerin 100.00 0.17 0.48 0.49 4.13 0.2% 15O-ii Myristic acid100.00 0.14 0.52 0.47 3.99 0.1% 15O-iii Moisture 100.00 0.15 0.48 0.513.91 100% 1 M 15O-i Glycerin 94.36 0.18 0.90 0.52 6.74 2.61 0.2% 15O-iiMyristic acid 94.23 0.11 1.11 0.51 6.51 2.52 0.1% 15O-iii Moisture 95.610.40 0.68 0.51 6.97 3.06 100% 2 M 15O-i Glycerin 97.31 0.18 1.26 0.536.37 2.24 0.2% 15O-ii Myristic acid 97.79 0.10 1.40 0.53 6.10 2.11 0.1%15O-iii Moisture 96.23 0.35 1.02 0.51 9.42 5.51 100% 3 M 15O-i Glycerin98.17 0.26 1.27 0.49 5.71 1.58 0.2% 15O-ii Myristic acid 98.05 0.16 1.310.51 5.55 1.56 0.1% 15O-iii Moisture 95.47 0.48 1.23 0.53 10.66 6.75100% 6 M 15O-i Glycerin 96.64 0.06 1.65 0.48 6.04 1.91 0.2% 15O-iiMyristic acid 96.76 0.01 1.68 0.47 5.71 1.72 0.1% 15O-iii Moisture 92.330.11 2.00 0.50 12.58 8.67 100%

The results of stability testing of Example 15O-i-iii at 55° C. are setforth in Table 241 below. TABLE 241 Monoethanolamine 0.5% TotalImpurities 55° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero15O-i Glycerin 100.00 0.17 0.48 0.49 4.13 0.2% 15O-ii Myristic acid100.00 0.14 0.52 0.47 3.99 0.1% 15O-iii Moisture 100.00 0.15 0.48 0.513.91 100% 1 W 15O-i Glycerin 96.03 0.17 0.77 0.28 5.96 1.83 0.2% 15O-iiMyristic acid 97.71 0.16 0.98 0.57 5.82 1.83 0.1% 15O-iii Moisture 96.840.01 0.60 0.59 6.94 3.03 100% 2 W 15O-i Glycerin 94.97 0.27 1.13 0.827.25 3.12 0.2% 15O-ii Myristic acid 96.86 0.18 1.38 0.60 6.74 2.75 0.1%15O-iii Moisture 96.28 0.18 0.91 0.53 8.37 4.46 100%

EXAMPLE 15P Dronabinol Solution in Sesame Oil Sourced from Arista withMonoethanolamine and Different Degradants Added

In Example 15P-i-iii, dronabinol formulations were prepared inaccordance with Example 15M-i-iii, respectively. The dronabinolformulations were then used to fill amber glass vials. The formulationswithin the vials were initially tested, then tested at 25° C. for 3 and6 months; 40° C. for 1, 2, 3 and 6 months and at 55° C. for 1 and 2weeks.

The results of stability testing of Example 15P-i-iii at 25° C. are setforth in Table 242 below. TABLE 242 Monoethanolamine 0.5% TotalImpurities 25° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero15P-i Glycerin 100.00 0.12 0.49 0.53 4.08 0.2% 15P-ii Myristic acid100.00 0.22 0.71 0.52 4.21 0.1% 15P-iii Moisture 100.00 0.16 0.49 0.564.23 100% 3 M 15P-i Glycerin 99.52 0.32 0.80 0.52 5.26 1.18 0.2% 15P-iiMyristic acid 101.10 0.37 0.96 0.52 5.52 1.31 0.1% 15P-iii Moisture98.53 0.14 0.61 0.56 6.86 2.63 100% 6 M 15P-i Glycerin 97.19 0.04 1.080.54 5.35 1.27 0.2% 15P-ii Myristic acid 99.58 0.03 1.20 0.51 4.85 0.640.1% 15P-iii Moisture 96.45 0.21 0.72 0.57 8.76 4.53 100%

The results of stability testing of Example 15P-i-iii at 40° C. are setforth in Table 243 below. TABLE 243 Monoethanolamine 0.5% TotalImpurities 40° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero15P-i Glycerin 100.00 0.12 0.49 0.53 4.08 0.2% 15P-ii Myristic acid100.00 0.22 0.71 0.52 4.21 0.1% 15P-iii Moisture 100.00 0.16 0.49 0.564.23 100% 1 M 15P-i Glycerin 94.91 0.06 0.73 0.54 5.67 1.59 0.2% 15P-iiMyristic acid 96.77 0.08 1.08 0.53 6.04 1.83 0.1% 15P-iii Moisture 93.950.28 0.72 0.54 9.73 5.50 100% 2 M 15P-i Glycerin 98.91 0.05 1.11 0.525.17 1.09 0.2% 15P-ii Myristic acid 99.74 0.07 1.52 0.49 5.17 0.96 0.1%15P-iii Moisture 94.59 0.43 1.07 0.42 10.64 6.41 100% 3 M 15P-i Glycerin97.29 0.01 1.54 0.55 6.39 2.31 0.2% 15P-ii Myristic acid 98.08 0.03 2.050.54 7.04 2.83 0.1% 15P-iii Moisture 92.40 0.25 1.40 0.52 13.24 9.01100% 6 M 15P-i Glycerin 92.84 0.04 2.84 0.56 9.73 5.65 0.2% 15P-iiMyristic acid 92.59 0.06 3.81 0.55 11.13 6.92 0.1% 15P-iii Moisture82.82 0.28 2.53 0.54 20.38 16.15 100%

The results of stability testing of Example 15P-i-iii at 55° C. are setforth in Table 244 below. TABLE 244 Monoethanolamine 0.5% TotalImpurities 55° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero15P-i Glycerin 100.00 0.12 0.49 0.53 4.08 0.2% 15P-ii Myristic acid100.00 0.22 0.71 0.52 4.21 0.1% 15P-iii Moisture 100.00 0.16 0.49 0.564.23 100% 1 W 15P-i Glycerin 96.64 0.15 0.86 0.59 5.53 1.45 0.2% 15P-iiMyristic acid 97.85 0.06 1.11 0.62 5.70 1.49 0.1% 15P-iii Moisture 95.510.02 0.62 0.59 8.55 4.32 100% 2 W 15P-i Glycerin 95.94 0.23 1.18 0.546.72 2.64 0.2% 15P-ii Myristic acid 97.85 0.32 1.57 0.52 6.87 2.66 0.1%15P-iii Moisture 94.83 0.34 0.93 0.57 10.24 6.01 100%

EXAMPLE 15Q Dronabinol Solution in Sesame Oil Sourced from Croda withMonoethanolamine and Different Degradants Added

In Example 15Q-i-iii, dronabinol formulations were prepared inaccordance with Example 15N-i-iii, respectively. The dronabinolformulations were then used to fill amber glass vials. The formulationswithin the vials were initially tested, then tested at 25° C. for 3 and6 months; 40° C. for 1, 2, 3 and 6 months and at 55° C. for 1 and 2weeks.

The results of stability testing of Example 15Q-i-iii at 25° C. are setforth in Table 245 below. TABLE 245 Monoethanolamine 0.5% TotalImpurities 25° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero15Q-i Glycerin 100.00 0.11 0.60 0.57 3.72 0.2% 15Q-ii Myristic acid100.00 0.11 0.66 0.54 4.02 0.1% 15Q-iii Moisture 100.00 0.10 0.58 0.573.53 100% 3 M 15Q-i Glycerin 100.62 0.10 0.81 0.58 5.57 1.85 0.2% 15Q-iiMyristic acid 99.22 0.21 0.97 0.59 5.64 1.62 0.1% 15Q-iii Moisture 90.310.40 0.55 0.59 13.92 10.39 100% 6 M 15Q-i Glycerin 97.99 0.04 1.05 0.625.61 1.89 0.2% 15Q-ii Myristic acid 97.90 0.03 1.19 0.56 5.43 1.41 0.1%15Q-iii Moisture 89.80 0.39 0.77 0.50 17.32 13.79 100%

The results of stability testing of Example 15Q-i-iii at 40° C. are setforth in Table 246 below. TABLE 246 Monoethanolamine 0.5% TotalImpurities 40° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero15Q-i Glycerin 100.00 0.11 0.60 0.57 3.72 0.2% 15Q-ii Myristic acid100.00 0.11 0.66 0.54 4.02 0.1% 15Q-iii Moisture 100.00 0.10 0.58 0.573.53 100% 1 M 15Q-i Glycerin 96.17 0.05 0.90 0.57 6.30 2.58 0.2% 15Q-iiMyristic acid 95.70 0.04 1.04 0.57 6.32 2.30 0.1% 15Q-iii Moisture 85.370.67 0.78 0.57 18.04 14.51 100% 2 M 15Q-i Glycerin 98.46 0.06 1.16 0.585.86 2.14 0.2% 15Q-ii Myristic acid 97.66 0.04 1.42 0.57 6.26 2.24 0.1%15Q-iii Moisture 85.46 0.81 1.14 0.53 20.45 16.92 100% 3 M 15Q-iGlycerin 97.24 0.01 1.53 0.59 6.82 3.10 0.2% 15Q-ii Myristic acid 95.960.01 2.01 0.58 7.87 3.85 0.1% 15Q-iii Moisture 52.14 1.21 3.06 0.6845.70 42.17 100% 6 M 15Q-i Glycerin 92.57 0.04 2.77 0.58 10.62 6.90 0.2%15Q-ii Myristic acid 89.50 0.05 4.14 0.59 13.37 9.35 0.1% 15Q-iiiMoisture — — — — — — 100%

The results of stability testing of Example 15Q-i-iii at 55° C. are setforth in Table 247 below. TABLE 247 Monoethanolamine 0.5% TotalImpurities 55° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero15Q-i Glycerin 100.00 0.11 0.60 0.57 3.72 0.2% 15Q-ii Myristic 100.000.11 0.66 0.54 4.02 acid 0.1% 15Q-iii 100.00 0.10 0.58 0.57 3.53Moisture 100% 1 W 15Q-i Glycerin 96.45 0.16 0.96 0.62 6.63 2.91 0.2%15Q-ii Myristic 95.76 0.29 1.09 0.61 6.19 2.17 acid 0.1% 15Q-iii 89.200.08 0.61 0.64 14.06 10.53 Moisture 100% 2 W 15Q-i Glycerin 94.40 0.321.40 0.59 7.80 4.08 0.2% 15Q-ii Myristic 95.41 0.13 1.53 0.59 7.54 3.52acid 0.1% 15Q-iii 89.05 0.53 0.86 0.64 16.18 12.65 Moisture 100%

EXAMPLE 15R Dronabinol Solution in Sesame Oil Sourced from Dipasa withMonoethanolamine and Different Degradants Added

In Example 15R-i-iii, dronabinol formulations were prepared inaccordance with Example 15O-i -iii, respectively. The dronabinolformulations were then used to fill amber glass vials. The formulationswithin the vials were initially tested, then tested at 25° C. for 3 and6 months; 40° C. for 1, 2, 3 and 6 months and at 55° C. for 1 and 2weeks.

The results of stability testing of Example 15R-i-iii at 25° C. are setforth in Table 248 below. TABLE 248 Monoethanolamine 0.5% TotalImpurities 25° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero15R-i Glycerin 100.00 0.17 0.48 0.49 4.13 0.2% 15R-ii Myristic acid100.00 0.14 0.52 0.47 3.99 0.1% 15R-iii Moisture 100.00 0.15 0.48 0.513.91 100% 3 M 15R-i Glycerin 98.81 0.37 0.76 0.54 6.15 2.02 0.2% 15R-iiMyristic acid 98.98 0.32 0.86 0.52 5.99 2.00 0.1% 15R-iii Moisture 99.920.18 0.57 0.53 6.55 2.64 100% 6 M 15R-i Glycerin 97.61 0.07 1.03 0.565.71 1.58 0.2% 15R-ii Myristic acid 98.05 0.03 1.13 0.53 5.46 1.47 0.1%15R-iii Moisture 97.15 0.29 0.77 0.56 8.43 4.52 100%

The results of stability testing of Example 15R-i-iii at 40° C. are setforth in Table 249 below. TABLE 249 Monoethanolamine 0.5% TotalImpurities 40° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero15R-i Glycerin 100.00 0.17 0.48 0.49 4.13 0.2% 15R-ii Myristic acid100.00 0.14 0.52 0.47 3.99 0.1% 15R-iii Moisture 100.00 0.15 0.48 0.513.91 100% 1 M 15R-i Glycerin 95.66 0.13 0.68 0.53 6.42 2.29 0.2% 15R-iiMyristic acid 96.09 0.09 0.98 0.53 6.50 2.51 0.1% 15R-iii Moisture 94.190.15 0.66 0.51 8.42 4.51 100% 2 M 15R-i Glycerin 98.85 0.10 1.17 0.485.23 1.10 0.2% 15R-ii Myristic acid 98.81 0.06 1.37 0.47 5.46 1.47 0.1%15R-iii Moisture 95.45 0.42 1.13 0.42 9.52 5.61 100% 3 M 15R-i Glycerin97.03 0.07 1.57 0.52 6.81 2.68 0.2% 15R-ii Myristic acid 96.95 0.01 1.940.52 7.21 3.22 0.1% 15R-iii Moisture 93.35 0.24 1.64 0.54 12.41 8.50100% 6 M 15R-i Glycerin 92.11 0.07 2.98 0.53 10.57 6.44 0.2% 15R-iiMyristic acid 90.40 0.08 3.90 0.55 12.37 8.38 0.1% 15R-iii Moisture82.67 0.38 2.91 0.56 21.52 17.61 100%

The results of stability testing of Example 15R-i-iii at 55° C. are setforth in Table 250 below. TABLE 250 Monoethanolamine Total Impurities0.5% 55° C. Potency % CBD % CBN % D8-THC % % Increase + % Zero 15R-iGlycerin 100.00 0.17 0.48 0.49 4.13 0.2% 15R-ii Myristic 100.00 0.140.52 0.47 3.99 acid 0.1% 15R-iii 100.00 0.15 0.48 0.51 3.91 Moisture100% 1 W 15R-i Glycerin 96.03 0.17 0.77 0.28 5.96 1.83 0.2% 15R-iiMyristic 97.71 0.16 0.98 0.57 5.82 1.83 acid 0.1% 15R-iii 96.84 0.010.60 0.59 6.94 3.03 Moisture 100% 2 W 15R-i Glycerin 94.97 0.27 1.130.82 7.25 3.12 0.2% 15R-ii Myristic 96.86 0.18 1.38 0.60 6.74 2.75 acid0.1% 15R-iii 96.28 0.18 0.91 0.53 8.37 4.46 Moisture 100%

As see from the results above, the protective effect of the basesmeglumine and monoethanolamine was confirmed by the addition ofdegradants such as glycerin, moisture, and myristic acid to thedronabinol formulation. The results above clearly indicate that thebases meglumine and monoethanolamine protect dronabinol formulationsfrom degradation induced by glycerin, moisture and myristic acid.

CONCLUSION

Many other variations of the present invention will be apparent to thoseskilled in the art and are meant to be within the scope of the claimsappended hereto. The foregoing specification alludes to beliefs,hypothesis and conclusions of the inventor based on his experience inthe field, the reports of others (such as those identified in thepublications identified herein), and experiments conducted and reportedherein, and are provided for purposes of (possible) explanation only andare not meant to limit the invention in any manner whatsoever.

REFERENCES

-   Armstrong N A, James K C, Pugh W K L. Drug migration into soft    gelatin capsule shells and its effect on in-vitro availability. J.    Pharm. Pharmacol. 36: 361-365, 1984-   Bauer K H. Die herstellung von hart- und weichgelatinekapseln. In:    Die Kapsel. Stuttgart: Wissenschaftliche Verlags GmbH. Editors:    Fahrig W, Hofer U H, 58-82, 1983.-   Beckstrom-Stenberg S M and Duke J A. “The phytochemical database.”    Ars-genome.cornell.edu/cgi-bin/WebAce/webace?db=phytochemdb. (Data    version July 1994).-   Bradley Morris J. Food, industrial, nutraceutical, and    pharmaceutical uses of sesame genetic resources. In: Trends in New    Crops and New Uses. Editors: Janick J and Whipkey A, 2002.-   Cade D, Cole E T, Mayer J-Ph, Wittwer F. Liquid filled and sealed    hard gelatin capsules. Acta Pharm. Technol. 29: 245-251, 1983.-   Ewart T. Cole. Liquid-filled and sealed hard gelatin capsule    technologies. In: Modified-Release Drug Delivery Technology.    Editors: Rathbone M J, Hadgraft J, Roberts M S, Publishers Marcel    Dekker, 2002.-   Featured Excipients: Antioxidants. Int. J. Pharm. Compounding. 3(1):    52-, January/February 1999.-   Hom F S, Veresh S A, Ebert W R. Soft gelatin capsules. II. Oxygen    permeability study of capsule shells. J. Pharm. Sci. 64(5): 851-857,    1975.-   Kato M J, Chu A, Davin L B. Lewis N G, Biosynthesis of antioxidant    lignans in sesamum indicum seeds. Phytochemisrty. 47: 583-591, 1998.-   Martin A, Bustamante P, and Chun AHC. Physical Pharmacy. Fourth ed.,    Lea & Febiger, 1993.-   Mechoulam R. Chemistry of cannabis. Handbook Exp. Pharmacol. 55:    119-134, 1981.-   Physicians Desk Reference®, ed. 2003.-   Shah N H, Phuarpradit W, Ahmed H. Liquid filling in hard gelatin    capsules: formulations and processing considerations. American    Pharmaceutical Review. 6(1): 14-21, Spring 2003.-   Sirato-Yasumoto S, Katsuta M, Okuyama Y, Takahashi Y, and Ide T.    Effect of sesame seeds rich in sesamin and sesamolin on fatty acid    oxidation in rat liver. J. Agr. Food Chem. 49: 2647-2651, 2001.-   U.S. Department of Health and Human Services, Food and Drug    Administration “Guidance for Industry: QIA (R2) Stability Testing of    New Drug Substances and Products.” ICH, November 2003.

All of the above references (patents and non-patent publications) arehereby incorporated by reference.

1. A cannabinoid dosage form comprising; an effective amount of apharmaceutically acceptable cannabinoid dispersed in a pharmaceuticallyacceptable oil-based carrier; and a hard gelatin capsule encapsulatingthe mixture of the cannabinoid and the oil-based carrier, said dosageform being stable at room temperature for at least one year.
 2. Thedosage form of claim 1, which contains at least about 80% w/w of thecannabinoid in undergraded form after exposure of the formulation tostorage conditions selected from the group consisting of (i) elevatedtemperature and humidity conditions of 40° C./75% relative humidity (RH)for 6 months; (ii) elevated temperature conditions of 55° C. for twoweeks; room temperature (25° C.) for two years; and any combinationthereof.
 3. The dosage form of claim 1, which contains at least about90% w/w of undegraded cannabinoid upon exposure of the formulation tostorage conditions selected from the group consisting of (i) elevatedtemperature and humidity conditions of 40° C./75% relative humidity (RH)for 6 months; (ii) elevated temperature conditions of 55° C. for twoweeks; room temperature (25° C.) for two years; and any combinationthereof.
 4. The dosage form of claim 1, wherein said cannabinoidcomprises dronabinol.
 5. The dosage form of claim 1, wherein saidoil-based carrier is a triglyceride selected from the group consistingof almond oil; babassu oil; borage oil; blackcurrant seed oil; canolaoil; castor oil; coconut oil; corn oil; cottonseed oil; evening primroseoil; grapeseed oil; groundnut oil; mustard seed oil; olive oil; palmoil; palm kernel oil; peanut oil; rapeseed oil; safflower oil; sesameoil; shark liver oil; soybean oil; sunflower oil; hydrogenated castoroil; hydrogenated coconut oil; hydrogenated palm oil; hydrogenatedsoybean oil; hydrogenated vegetable oil; hydrogenated cottonseed andcastor oil; partially hydrogenated soybean oil; soy oil; glyceryltricaproate; glyceryl tricaprylate; glyceryl tricaprate; glyceryltriundecanoate; glyceryl trilaurate; glyceryl trioleate; glyceryltrilinoleate; glyceryl trilinolenate; glyceryl tricaprylate/caprate;glyceryl tricaprylate/caprate/laurate; glyceryltricaprylate/caprate/linoleate; glyceryl tricaprylate/caprate/stearate;saturated polyglycolized glycerides; linoleic glycerides;caprylic/capric glycerides; modified triglycerides; fractionatedtriglycerides; and mixtures thereof.
 6. The dosage form of claim 4,wherein said oil-based carrier comprises sesame oil.
 7. The dosage formof claim 6, wherein said sesame oil is selected from a Food Grade sesameoil or a NF grade sesame oil.
 8. The dosage form of claim 1, whereinsaid oil-based carrier is selected from the group consisting of soybeanoil, olive oil, cotton seed oil, peanut oil, sesame oil, castor oil, andmixtures of any of the foregoing.
 9. The dosage form of claim 1, whichcomprises from about 0.05 to about 90% cannabinoid, by weight.
 10. Thedosage form of claim 1, which comprises from about 0.1% to about 50%cannabinoid, by weight.
 11. The dosage form of claim 1, which comprisesfrom about 1.5 to about 6% cannabinoid, by weight.
 12. The dosage formof claim 1, which comprises from about 2.5% to about 4.5% cannabinoid byweight.
 13. The dosage form of claim 6, wherein said sesame oil containsan effective amount of an anti-oxidant selected from the groupconsisting of sesamin, sesamol, sesamolin, lecithin and any combinationof the foregoing.
 14. The dosage form of claim 1, which contains aneffective amount of one or more anti-oxidants to promote stability ofthe cannabinoid against unacceptable degradation.
 15. The dosage form ofclaim 14, which comprises from about 0.001% to about 10% anti-oxidant,by weight.
 16. The dosage form of claim 2, wherein the cannabinoid isdronabinol and does not contain unacceptable levels of dronabinoldegradants in the dosage form selected from the group consisting ofgreater than 2% delta-8 tetrahydrocannabinol (D8THC), greater than 2%cannabinol (CBN), greater than 2% cannabidiol (CBD), and any combinationthereof.
 17. The dosage form of claim 1, which contains an effectiveamount of one or more organic bases to promote stability of thecannabinoid against unacceptable degradation.
 18. The dosage form ofclaim 17, which comprises from about 0.001% w/w to about 5% organicbase, by weight.
 19. The dosage form of claim 17, which comprises fromabout 0.007% w/w to about 2% organic base, by weight.
 20. The dosageform of claim 17, wherein said organic base is selected from the groupconsisting of ethanolamine, methanolamine, meglumine, and anycombination of the foregoing.
 21. The dosage form of claim 1, whereinsaid hard gelatin capsule contains from about 85% to about 100% gelatinand from about 1% to about 15% water, by weight.
 22. The dosage form ofclaim 14, wherein said anti-oxidant comprises lecithin, said dosage fromcomprising from about 0.1% to about 10% lecithin, by weight.
 23. Thedosage form of claim 22, wherein said lecithin is included in an amountfrom about 0.3% to about 8.25%, by weight.
 24. The dosage form of claim12, wherein said anti-oxidant is L-ascorbic acid-6-palmitate in anamount from about 0.001% to about 1%, by weight.
 25. The dosage form ofclaim 24, wherein said L-ascorbic acid-6-palmitate is in an amount fromabout 0.01% to about 0.1%, by weight.
 26. The dosage form of claim 1,wherein the anti-oxidant is selected from the group consisting of butylhydroxyl anisole (BHA), butyl hydroxyl toluene (BHT), propyl gallate,lecithin, Vitamin E tocopherol, sesamin, sesamol, sesamolin, alphatocopherol, ascorbic acid, ascorbyl palmitate, fumaric acid, malic acid,sodium ascorbate and sodium metabisulphite, disodium EDTA, andcombinations of any of the foregoing.
 27. The dosage form of claim 1,which further comprises one or more additional therapeutically activeagents.
 28. The dosage form of claim 27, wherein said additionaltherapeutically active agent is selected from a narcotic analgesic, anon-narcotic analgesic, an anti-emetic, a steroid, and mixtures of anyof the foregoing.
 29. The dosage form of claim 1, wherein thecannabinoid is dronabinol in an amount from about 0.05 mg to about 20mg.
 30. The dosage form of claim 1 which contains dronabinol as theactive ingredient, the dosage form containing ingredients at a levelselected from the following during its claimed shelf-life as follows:(i) not less than 90% of the initial dronabinol content; (ii) notgreater than about 2% cannabinol; (iii) not greater than about 2%cannabidiol; (iv) not greater than about 2% delta-8-THC; (v) not greaterthan about 0.5% exo-THC; and (vi) any combination of the foregoing. 31.The dosage form of claim 30, wherein the oil-based carrier is sesameoil.
 32. The dosage form of claim 1, wherein the oil-based carriercomprises a semi-solid lipophilic material selected from the groupconsisting of arachis oil (Groundnut 36); castor oil (Cutina HR);cottonseed oil (Sterotex); palm oil (Softisan 154); soybean oil (Alkosol407).
 33. The dosage form of claim 32, which further comprises aneffective amount of a viscosity modifier to provide a pharmaceuticallyacceptable viscosity to the cannabinoid dispersed in the oil-basedcarrier, said viscosity modifier selected from the group consisting ofAerosil (silicon dioxide); cetostearyl alcohol; cetyl alcohol; stearylalcohol; Gelucire 33/01; Gelucire 39/01; Gelucire 43/01; glycerylbehenate (Compritol 888 ATO); glyceryl palmitostearate (Precirol AT05);Softisan 100; Softisan 142; Softisan 378; Softisan 649; and mixturesthereof.
 34. The dosage form of claim 1, which further comprises aneffective amount of a solubilizer for said cannabinoid.
 35. The dosageform of claim 1, which further comprises an emulsifier.
 36. The dosageform of claim 1, which further comprises an absorption enhancer.
 37. Thedosage form of claim 1, which further comprises a surfactant.
 38. Thedosage form of claim 1, which further includes a stabilizer whichstabilizes the cannabinoid against unacceptable degradation.
 39. Thedosage form of claim 6, wherein the sesame oil is an NF grade sesameoil.
 40. The formulation of claim 6, wherein the sesame oil contains ananti-oxidant selected from the group consisting of sesamin, sesamol,sesamolin, lecithin and any combination of the foregoing.
 41. The dosageform of claim 6, wherein the sesame oil is a refined grade to which asufficient amount of anti-oxidant has been added to promote stability ofthe cannabinoid in the dosage form.
 42. The dosage form of claim 4,wherein the dronabinol is from a source selected from the groupconsisting of a natural source, a synthetic source, a semi-syntheticsource, and a mixture of any of the foregoing.
 43. The dosage form ofclaim 1, wherein the cannabinoid is in a form selected from the groupconsisting of its free form, a salt, an ester, a prodrug, a complex, anda mixture of any of the foregoing.
 44. The dosage form of claim 14,which contains an effective amount of one or more organic bases topromote stability of the cannabinoid against unacceptable degradation.45. The dosage form of claim 1, wherein said formulation is homogeneousand thermodynamically stable.
 46. The dosage form of claim 1, in whichthe formulation contains at least about 90% w/w of the cannabinoid inundegraded form after exposure of the formulation to storage conditionsselected from the group consisting of (i) elevated temperature andhumidity conditions of 40° C./75% relative humidity (RH) for 6 months;(ii) elevated temperature conditions of 55° C. for two weeks; roomtemperature (25° C.) for two years; and any combination thereof.
 47. Aroom-temperature stable formulation of a cannabinoid, comprising atherapeutically effective amount of a cannabinoid dispersed in anoil-based carrier contained in a unit dose enclosure, said unit doseenclosure composed of one or more materials which do not react with thecannabinoid or allow substantial permeation of oxygen and whicheffectively seals the cannabinoid from moisture, such that thecannabinoid in the formulation is protected against unacceptabledegradation and at least about 80% w/w of the cannabinoid is maintainedin undegraded form after exposure of the formulation to storageconditions selected from the group consisting of (i) controlledtemperature and humidity conditions of 25° C./60% relative humidity(RH), (ii) controlled temperature and humidity conditions of 30° C./60%relative humidity (iii) elevated temperature and humidity conditions of40° C./75% relative humidity (RH) for 6 months; (iv) elevatedtemperature conditions of 55° C. for two weeks; room temperature (25°C.) for two years; and any combination thereof.
 48. The formulation ofclaim 47, wherein the cannabinoid is dronabinol derived from a sourceselected from the group consisting of a natural source, a syntheticsource, a semi-synthetic source, and a mixture of any of the foregoing.49. The formulation of claim 48, wherein the oil-based carrier is sesameoil.
 50. The formulation of claim 49, wherein the sesame oil contains ananti-oxidant selected from the group consisting of sesamin, sesamol,sesamolin, lecithin and any combination of the foregoing.
 51. Theformulation of claim 49, wherein the sesame oil is a refined grade towhich a sufficient amount of anti-oxidant has been added to promotestability of the cannabinoid in the dosage form.
 52. The formulation ofclaim 47, wherein the the oil-based carrier comprises a semi-solidlipophilic material selected from the group consisting of arachis oil(Groundnut 36); castor oil (Cutina HR); cottonseed oil (Sterotex); palmoil (Softisan 154); soybean oil (Alkosol 407).
 53. The formulation ofclaim 52, which further comprises an effective amount of a viscositymodifier to provide a pharmaceutically acceptable viscosity to thecannabinoid dispersed in the oil-based carrier, said viscosity modifierselected from the group consisting of Aerosil (silicon dioxide);cetostearyl alcohol; cetyl alcohol; stearyl alcohol; Gelucire 33/01;Gelucire 39/01; Gelucire 43/01; glyceryl behenate (Compritol 888 ATO);glyceryl palmitostearate (Precirol AT05); Softisan 100; Softisan 142;Softisan 378; Softisan 649; and mixtures thereof.
 54. The formulation ofclaim 47; further comprising a pharmaceutical excipient selected fromthe group consisting of viscosity modifiers; solubilizers; stabilizers;surfactants; emulsifiers, absorption enhancers, and mixtures thereof.55. The formulation of claim 47, wherein the oil-based carrier is alipophilic liquid is selected from the group consisting of arachis oil;castor oil; cottonseed oil; maize (corn) oil; olive oil; sesame oil;soybean oil; sunflower oil; Alkomed E and Alkomed R; Captex 355;Labrafac CC and Labrafac PG; Lauroglycol FCC; Miglyol 810; Miglyol 812;Miglyol 829; Miglyol 840; Softisan 645; and mixtures thereof.
 56. Theformulation of claim 48, wherein the cannabinoid is dronabinol in anamount from about 2.5 mg to about 20 mg.
 57. The formulation of claim47, wherein the unit dose enclosure is a capsule having a coating on itssurface selected from the group consisting of an enteric coating, a sealcoating, or both.
 58. The formulation of claim 47, wherein the unit doseenclosure is selected from the group consisting of a starch capsule; acellulosic capsule; a hydrocolloid film-forming composition comprising amixture of iota carrageenan, a bulking agent and kappa carrageenan; anda hard gelatin capsule.
 59. The formulation of claim 50, wherein theunit dose enclosure is a sealed hard gelatin capsule.
 60. A formulationof a therapeutically effective amount of an encapsulated cannabinoid andmeans for stabilizing the cannabinoid, such that the formulationcontains at least about 80% w/w of the cannabinoid in undegraded formafter exposure of the formulation to storage conditions selected fromthe group consisting of (i) elevated temperature and humidity conditionsof 40° C./75% relative humidity (RH) for 6 months; (ii) elevatedtemperature conditions of 55° C. for two weeks; room temperature (25°C.) for at least one year; and any combination thereof.
 61. Theformulation of claim 60, wherein said means for stabilizing thecannabinoid comprises a hard gelatin capsule.
 62. The formulation ofclaim 60, wherein said means for stabilizing the cannabinoid comprisesan effective amount of an anti-oxidant.
 63. The formulation of claim 60,wherein said means for stabilizing the cannabinoid comprises aneffective amount of an organic base.
 64. The formulation of claim 60,wherein said means for stabilizing the cannabinoid comprises aneffective amount of at least one anti-oxidant together with an effectiveamount of an organic base.
 65. The formulation of claim 60, wherein saidmeans for stabilizing the cannabinoid comprises a starch capsule. 66.The formulation of claim 65, wherein said means for stabilizing thecannabinoid further comprises an effective amount of at least oneanti-oxidant, an effective amount of an organic base, or both.
 67. Theformulation of claim 60, wherein said means for stabilizing thecannabinoid comprises a cellulosic capsule.
 68. The formulation of claim67, wherein said means for stabilizing the cannabinoid further comprisesan effective amount of at least one anti-oxidant, an effective amount ofan organic base, or both.
 69. The formulation of claim 60, wherein saidmeans for stabilizing the cannabinoid comprises a non-animal basedhydrocolloid film-forming composition for use in the manufacture ofencapsulated dosage forms.
 70. The formulation of claim 69, wherein saidmeans for stabilizing the cannabinoid further comprises an effectiveamount of at least one anti-oxidant, an effective amount of an organicbase, or both.
 71. The formulation of claim 69, wherein saidhydrocolloid film-forming composition comprises a mixture of iotacarrageenan, a bulking agent and kappa carrageenan.
 72. The formulationof claim 60, wherein said means for stabilizing the cannabinoidcomprises an oil-based carrier containing an effective amount of atleast one anti-oxidant.
 73. The formulation of claim 72, wherein saidmeans for stabilizing the cannabinoid further comprises an encapsulationcomposed of one or more materials which do not react with thecannabinoid or allow substantial permeation of oxygen and whicheffectively seals the cannabinoid from moisture.
 74. The formulation ofclaim 60, wherein said cannabinoid is dronabinol, and wherein after twoyears of storage at room temperature the dosage form contains (i) notless than 90% of the initial dronabinol content; (ii) not greater thanabout 2% cannabinol; (iii) not greater than about 2% cannabidiol; (iv)not greater than about 2% delta-8-THC; and (v) any combination of theforegoing.
 75. The formulation of claim 73, wherein the cannabinoid isdronabinol.
 76. The formulation of claim 60, where the dosage formcontains dronabinol as the active ingredient, the dosage form containingingredients at a level selected from the following during its claimedshelf-life: (i) not less than 90% of the initial dronabinol content;(ii) not greater than about 2% cannabinol; (iii) not greater than about2% delta-8-THC; (iv) not greater than about 0.5% exo-THC; and anycombination of the foregoing.
 77. The formulation of claim 76, whereinthe cannabinoid is dronabinol in an amount from about 2.5 mg to about 20mg.
 78. A room-temperature stable cannabinoid formulation comprising asealed hard gelatin capsule containing a therapeutically effectiveamount of a pharmaceutically acceptable cannabinoid in an oil-basedcarrier.
 79. The formulation of claim 78, wherein the cannabinoid isdronabinol derived from a source selected from the group consisting of anatural source, a synthetic source, a semi-synthetic source, and amixture of any of the foregoing.
 80. The formulation of claim 79,wherein the oil-based carrier is sesame oil.
 81. The formulation ofclaim 80, wherein the sesame oil contains an anti-oxidant selected fromthe group consisting of sesamin, sesamol, sesamolin, lecithin and anycombination of the foregoing.
 82. The formulation of claim 78, whereinthe oil-based carrier further comprises an organic base is selected fromthe group consisting of ethanolamine, methanolamine, meglumine, and anycombination of the foregoing.
 83. The formulation of claim 78, whereinthe cannabinoid is dronabinol and does not contain unacceptable levelsof dronabinol degradants in the dosage form selected from the groupconsisting of greater than 2% delta-8 tetrahydrocannabinol (D8THC),greater than 2% cannabinol (CBN), greater than 2% cannabidiol (CBD), andany combination thereof, when the dosage form is stored at roomtemperature for two years.
 84. The formulation of claim 79, whichcomprises from about 1.5 to about 6% dronabinol, by weight.
 85. Theformulation of claim 79, wherein the dronabinol is in a form selectedfrom the group consisting of its free form, a salt, an ester, a prodrug,a complex, and a mixture of any of the foregoing.
 86. A stabilized oraldosage form of a cannabinoid, comprising a mixture of a therapeuticallyeffective amount of a cannabinoid dispersed in an oil-based carriercontained in unit dosage form selected from a hard gelatin capsule, acellulosic capsule, a starch capsule, and a non-animal basedhydrocolloid film-forming composition.
 87. The stabilized oral dosageform of claim 86, wherein said oil-based carrier further comprises astabilizer for the cannabinoid.
 88. A stabilized cannabinoid dosage formprepared by utilizing liquid filled hard gelatin technology to obtain adosage form in which the cannabinoid remains within about 90% to about110% percent of its initial amount incorporated in the dosage form forat least about 2 years after manufacture.
 89. A stabilized oral dosageform of a cannabinoid, comprising a therapeutically effective amount ofa cannabinoid dispersed in an oil-based carrier and encapsulated withina soft gelatin capsule, said oil-based carrier containing an effectiveamount of a stabilizer for the cannabinoid to provide a room-temperaturestable formulation for at least one year, such that the cannabinoidremains within about 90% to about 110% percent of its initial amountincorporated in the dosage form for at least 1 year after manufacture.90. A method for stabilizing an oral dosage form containing acannabinoid; comprising incorporating a therapeutically effective amountof a cannabinoid dispersed in an oil-based carrier into a unit dosageform suitable for oral administration, said unit dosage form consistingof a material selected from a hard gelatin capsule, a cellulosiccapsule, a starch capsule, and a non-animal based hydrocolloidfilm-forming composition.
 91. A method for stabilizing a dosage formcontaining a cannabinoid as the active pharmaceutical ingredient,comprising encapsulating a therapeutically effective amount of thecannabinoid in a liquid filled hard gelatin capsule.
 92. The method ofclaim 91, wherein said liquid is a pharmaceutically acceptable oil-basedcarrier which includes a stabilizer to promote the stability of thecannabinoid selected from the group consisting of an effective amount ofone or more anti-oxidants, one or more organic bases, and combinationsthereof.
 93. The method of claim 92, wherein the oil-based carrier islecithin.
 94. A method for stabilizing a dosage form containing acannabinoid as the active pharmaceutical ingredient, comprisingencapsulating a therapeutically effective amount of the cannabinoid in apharmaceutically acceptable oil-based carrier containing an effectiveamount of one or more anti-oxidants.
 95. The method of claim 94, whereinthe anti-oxidant is selected from the group consisting of sesamin,sesamol, sesamolin, lecithin and any combination of the foregoing. 96.The method of claim 94, further comprising adding an effective amount ofone or more organic bases to said oil-based carrier.
 97. The formulationof claim 96, wherein the organic base is selected from the groupconsisting of ethanolamine, methanolamine, meglumine, and anycombination of the foregoing.
 98. A method for stabilizing a dosage formcontaining a cannabinoid as the active pharmaceutical ingredient,comprising encapsulating a therapeutically effective amount of thecannabinoid in a pharmaceutically acceptable oil-based carriercontaining an amount of one or more organic bases that is effective tostabilize the cannabinoid.
 99. A method for preparing a stabilizeddosage form containing a cannabinoid as the active pharmaceuticalingredient, comprising mixing a solution of a cannabinoid with anoil-based carrier to obtain a flowable mixture; filling anappropriately-sized hard gelatin capsule with a quantity of said mixturethat contains a desired therapeutically effective amount of saidcannabinoid; and sealing the hard gelatin capsule.
 100. The method ofclaim 99, further comprising adding an effective amount of one or morestabilizers into the mixture prior to filling the hard gelatin capsule,the stabilizers promoting the stability of the cannabinoid againstdegradation over the claimed shelf life of the stabilized dosage form.101. The method of claim 99, further comprising subjecting thestabilized formulation to stability testing selected from the groupconsisting of: (i) elevated temperature and humidity conditions of 40°C./75% relative humidity (RH) for 6 months; (ii) elevated temperatureconditions of 55° C. for two weeks; room temperature (25° C.) for twoyears; and any combination thereof.
 102. The method of claim 101,further comprising adding an effective amount of one or more stabilizersinto the mixture prior to filling the hard gelatin capsule, thestabilizers promoting the stability of the cannabinoid againstdegradation over the claimed shelf life of the stabilized dosage form.103. The method of claim 100, wherein the at least one stabilizer isselected from the group consisting of an anti-oxidant, an organic base,and mixtures thereof.
 104. The method of claim 99, wherein thecannabinoid is dronabinol, further comprising testing the stabilizedformulation to ensure that two years of storage at room temperature thedosage form contains (i) not less than 90% of the initial dronabinolcontent; (ii) not greater than about 2% cannabinol; (iii) not greaterthan about 2% cannabidiol; (iv) not greater than about 2% delta-8-THC;and (v) any combination of the foregoing.
 105. A method for preparing astabilized dosage form containing a cannabinoid as the activepharmaceutical ingredient, comprising mixing a solution of a cannabinoidwith an oil-based carrier to obtain a flowable mixture; encapsulating aquantity of the mixture containing a desired therapeutically effectiveamount of said cannabinoid within a non-glycerin based compositioncomposed of one or more materials which do not react with thecannabinoid or allow substantial permeation of oxygen and whicheffectively seals the cannabinoid from moisture.
 106. A stabilized oraldosage form of dronabinol, comprising from about 0.05 mg to about 20 mgdronabinol dispersed in sesame oil, the concentration of dronabinol inthe sesame oil being from about 1.5% to about 6% by weight, encapsulatedin a sealed hard gelatin capsule.
 107. The stabilized oral dosage formof claim 105, wherein the stabilized dosage form contains at least about90% w/w of undegraded dronabinol upon exposure of the formulation tostorage conditions selected from the group consisting of (i) elevatedtemperature and humidity conditions of 40° C./75% relative humidity (RH)for 6 months; (ii) elevated temperature conditions of 55° C. for twoweeks; room temperature (25° C.) for two years; and (iii) anycombination thereof.
 108. The stabilized oral dosage form of claim 107,wherein the sesame oil contains an effective amount of a stabilizer topromote the stability of the dronabinol.
 109. The stabilized oral dosageform of claim 108, wherein the stabilizer is an anti-oxidant in anamount from about 0.001% to about 10%, by weight.
 110. The stabilizedoral dosage form of claim 109, wherein the anti-oxidant is selected fromthe group consisting of sesamin, sesamol, sesamolin, lecithin and anycombination of the foregoing.
 111. The stabilized oral dosage form ofclaim 110, wherein the anti-oxidant comprises lecithin in an amount fromabout 0.3% to about 8.25%, by weight.
 112. The stabilized oral dosageform of claim 108, wherein the stabilizer comprises an organic base inan amount from about 0.001% w/w to about 5%, by weight.
 113. Thestabilized oral dosage form of claim 112, wherein the organic base isselected from the group consisting of ethanolamine, methanolamine,meglumine, and any combination of the foregoing.
 114. The stabilizedoral dosage form of claim 106, further comprising one or more additionaltherapeutically active agents.
 115. The stabilized oral dosage form ofclaim 106, wherein the dronabinol is from a source selected from thegroup consisting of a natural source, a synthetic source, asemi-synthetic source, and a mixture of any of the foregoing.
 116. Thedosage form of claim 106, wherein the dronabinol is in a form selectedfrom the group consisting of its free form, a salt, an ester, a prodrug,a complex, and a mixture of any of the foregoing.
 117. The dosage formof claim 1, wherein the oil-based carrier is lecithin.
 118. The dosageform of claim 1, further comprising an effective amount of a stabilizerto promote the stability of the cannabinoid in the formulation, thestabilizer being selected from the group consisting of one or moreanti-oxidants, one or more organic bases, and combinations thereof. 119.The dosage form of claim 47, wherein the oil-based carrier is lecithin.120. The dosage form of claim 47, further comprising an effective amountof a stabilizer to promote the stability of the cannabinoid in theformulation, the stabilizer being selected from the group consisting ofone or more anti-oxidants, one or more organic bases, and combinationsthereof.